Closed-loop vagus nerve stimulation

ABSTRACT

Devices, systems and methods for the treatment of chronic inflammatory disorders that include an implantable microstimulator and an external charger/controller wherein the microstimulator is configured to operate using closed-loop feedback. The feedback for the microstimulator can be electrical activity of the vagus nerve and/or heart sensed by the microstimulator. The feedback can be used to modulate the stimulation duration, intensity, frequency, on-time and off-time.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/782,715, filed on Oct. 6, 2015, now U.S. Patent Publication No.US-2016-0067497-A1, which is a national phase application under 35 USC371 of International Patent Application No. PCT/US2014/033690, filed onApr. 10, 2014, now PCT Patent Publication No. WO 2014/169145, whichclaims priority to U.S. Provisional Patent Application No. 61/810,690,filed Apr. 10, 2013, each of which is herein incorporated by referencein its entirety.

Some variations of the methods and apparatuses described in this patentapplication may be related to the following U.S. patent applications:U.S. patent publication no. US-2010-0125304, filed on Nov. 17, 2009 andtitled, “DEVICES AND METHODS FOR OPTIMIZING ELECTRODE PLACEMENT FORANTI-INFLAMATORY STIMULATION,” now U.S. patent Ser. No. 12/620,413; U.S.patent publication no. US-2011-0054569, filed on Sep. 1, 2010 andtitled, “PRESCRIPTION PAD FOR TREATMENT OF INFLAMMATORY DISORDERS”; U.S.patent publication no. US-2011-0106208, filed on Nov. 1, 2010 andtitled, “MODULATION OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY TOTREAT PAIN OR ADDICTION,” now U.S. Pat. No. 8,996,116; U.S. patentpublication no. US-2011-0190849, filed on Dec. 23, 2010 and titled,“NEURAL STIMULATION DEVICES AND SYSTEMS FOR TREATMENT OF CHRONICINFLAMMATION,” now U.S. Pat. No. 8,612,002; U.S. patent publication no.US-2010-0312320, filed on Jun. 9, 2010 and titled, “NERVE CUFF WITHPOCKET FOR LEADLESS STIMULATOR,” now U.S. Pat. No. 8,886,339; U.S.patent publication no. US-2012-0290035, filed on May 9, 2012 and titled,“SINGLE-PULSE ACTIVATION OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY TOTREAT CHRONIC INFLAMMATION,” now U.S. Pat. No. 8,788,034; and U.S.patent publication no. US 2013-0079834, filed on Dec. 27, 2011 andtitled, “MODULATION OF SIRTUINS BY VAGUS NERVE STIMULATION,” now U.S.patent Ser. No. 13/338,185. Each of these patent applications is hereinincorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Described herein are apparatuses and methods for treatment of chronicinflammation. In particular, described herein are systems including animplantable microstimulators adapted for electrically stimulating one ormore nerves (e.g., the vagus nerve) to treat chronic inflammation bymodulation of the inflammatory response (via the nicotinic cholinergicanti-inflammatory pathway) using closed-loop stimulation.

BACKGROUND

Implantable electrical stimulation devices have been developed fortherapeutic treatment of a wide variety of diseases and disorders. Forexample, implantable cardioverter defibrillators (ICDs) have been usedin the treatment of various cardiac conditions. Spinal cord stimulators(SCS), or dorsal column stimulators (DCS), have been used in thetreatment of chronic pain disorders including failed back syndrome,complex regional pain syndrome, and peripheral neuropathy. Peripheralnerve stimulation (PNS) systems have been used in the treatment ofchronic pain syndromes and other diseases and disorders. Functionalelectrical stimulation (FES) systems have been used to restore somefunctionality to otherwise paralyzed extremities in spinal cord injurypatients.

Typical implantable electrical stimulation systems can include a systemwith one or more programmable electrodes on a lead that are connected toan implantable pulse generator (IPG) that contains a power source andstimulation circuitry. However, these systems can be difficult and/ortime consuming to implant, as the electrodes and the IPG are usuallyimplanted in separate areas and therefore the lead must be tunneledthrough body tissue to connect the IPG to the electrodes. Also, leadsare susceptible to mechanical damage over time as they are typicallythin and long. Most significantly to this disclosure, the controllersare typically open loop, meaning that they do not adapt stimulationbased on feedback from the vagus nerve itself, and/or the effect on theinflammatory response.

Recently, small implantable neural stimulator technology, i.e.microstimulators, having integral electrodes attached to the body of astimulator has been developed to address the disadvantages describedabove. This technology allows the typical IPG, lead and electrodesdescribed above to be replaced with a single device Elimination of thelead has several advantages including reduction of surgery time byeliminating, for example, the need for implanting the electrodes and IPGin separate places, the need for a device pocket, tunneling to theelectrode site, and strain relief ties on the lead itself. Reliabilityis therefore increased significantly, especially in soft tissue andacross joints because active components, such as lead wires, are nowpart of the rigid structure and are not subject to the mechanical damagedue to repeated bending or flexing over time.

However, the devices described to date continue to be open-loop devices,or do not regulate the stimulation based on feedback from the vagusnerve, including spiking/burst patterns, or the like. Based on recentexperimental data suggesting desensitization, as well aspatient-to-patient variability, such open-loop stimulation, or evenclosed-loop stimulation that is based on incorrect monitoringparameters, may result in less effective (or even ineffective)treatment, particularly when treating inflammation.

For example, FIGS. 41A and 41B describes the effect of repeated VNSstimulation, and looks at the resulting modulation of TNF (as %baseline). These results suggest that repeated dosing may alter theeffect of VNS in modulating inflammation, and further, that this effectmay be highly variable among individuals in a population and may resultin tachyphylaxis of the cholinergic anti-inflammatory pathway. Inaddition, the stimulation required to modulate different individuals maybe variable between individuals. For example, FIG. 15 illustrates theeffect of a single superathreshold VNS pulse to activate ananti-inflammatory response.

Thus, there remains a need for a leadless integral device that is stablypositioned on the nerve, and can provide for removal and/or replacementof the stimulation device with relative ease, which can be controlled inan energy-efficient, as well as efficacious manner, e.g., using aclosed-loop feedback system and method.

SUMMARY OF THE DISCLOSURE

Described herein are devices systems and methods for the treatment ofchronic inflammatory disorders that include an implantablemicrostimulator and an external charger/controller wherein thecontroller is configured to operate using closed-loop feedback. Further,the implantable microstimluator may be configured to both applystimulation and to receive/record activity on the nerve (bundled) withinthe microstimulator. In some variations a separate controller (e.g.,“prescription pad”) may also be included as part of the system andadapted for use with the closed-loop feedback methods described herein,as well as for recording/transmitting and/or analyzing the sensedactivity from the vagus nerve.

Although the examples and descriptions described herein are generallyrelated primarily to treatment of inflammation it is not limited tothis. VNS, including the very low duty-cycle VNS described herein, maybe used for other indications, including modulation of sirtuins, andmodulation of osteoblast activation (e.g., RANKL, OPG AND OPG/RANKLRATIO, etc.)

Any of the microstimulators described may be modified as described andillustrated in FIGS. 45-54. Furthermore, any of the methods describedherein may be modified to include closed-loop stimulation.

In some variations, the microstimulator may include two (or more) partsthat may assemble in-situ, in the operating room, or during themanufacturing process. The microstimulator (or “microstimulator system”)may include a nerve cuff with or without integral electrodes, which maybe called a POD (“Protection and Orientation Device,” e.g., see FIGS.5A-D and U.S. patent publication no. US-2010-0312320, titled “NERVE CUFFWITH POCKET FOR LEADLESS STIMULATOR,” now U.S. Pat. No. 8,886,339,previously incorporated by reference) that may enclose a portion of theneural tissue, and a microstimulator. The microstimulator (e.g., FIG. 4)generally includes integral contacts that make contact with the neuraltissue, and if used in conjunction with a POD, may also make contactwith the integral contacts within the POD.

The POD cuff electrode configuration of the stimulation device may allowthe device to be stably positioned proximate a nerve, such as the vagusnerve. Furthermore, the cuff electrode configuration may also have thecharacteristics of driving most of the current into the nerve, whileshielding surrounding tissues from unwanted stimulation.

In some embodiments, the nerve cuff generally includes a polymer cuffbody or carrier, such as Silastic® cuff or sleeve, having a pocket orpouch defined therein for irremovably receiving a leadless stimulationdevice. The leadless stimulation device is positioned within the pocketor sleeve such that the electrodes of the device are positionedproximate the nerve to be stimulated and in alignment with integralcontacts. The pocket can be defined by the space between the stimulationdevice and an inner surface of the cuff body or can comprise apouch-like structure attached to the cuff body for containing thestimulation device. The nerve cuff can configured to be coupled to thenerve, or to a surrounding sheath that contains the nerve, or to both,depending on the desired level of stability.

The nerve cuff can be implanted by first dissecting the nerve to whichit is to be connected, such as the vagus nerve, from its surroundingsheath, wrapping the nerve cuff around the nerve, optionally coupling orsuturing the nerve cuff to one of either the nerve or the sheath andinserting the stimulation device within the pocket or pouch of the cuffbody such that the stimulation device is proximate the nerve, orallowing the whole cuff and stimulation device to float along the axisof the nerve allowing fibrous encapsulate the device and eliminate orreduce movement of the device up and down along the nerve, and rotatingaround the neural axis.

The POD may be constructed with a biocompatible and durable polymer(FIGS. 5A-D). It is designed to be thin as possible to minimizedisplacement of nearby tissues to not be excessively more than themicrostimulator itself. Other design goals include smooth and gradualtransitions between surfaces to avoid anatomical damage or irritation.Support to easily allow replacement of the microstimulator; this can beenabled through top access over the nerve and securing device in the PODby sutures. Suture holes may be implemented to guide the surgeon, andembedded Dacron may be used to reinforce those openings. Mechanically(interlocking) and visually keyed (colored stripes) may be used so thatwhen sutured shut, deformation or misalignment will not occur. Designshould be such that over-tightening sutures do not compress the nerveleading to de-vascularization and eventual nerve death. In thisembodiment, this is achieved by creating a rigid or semi-rigid nervechannel in the microstimulator itself. Nerve diameters of 2-4 mm fromround to oval shapes require support; an oval shape is preferred in thisimplementation. The contacts should be protected from fibrous in growthvia the POD as well as shielding non-target tissues. A polymericmaterial is choosing to further protect the surround the rigid MEB fromsoft tissue. The POD maintains co-axial alignment with the target nerve.The POD design is such that the POD may move up and down on nerve andmay rotate around the nerve, and as mentioned earlier this iscompensated through the use of non-coplanar antennae.

The POD may contain integral electrodes. This provides the opportunityto completely encircle the nerve. A platinum alloy may be embedded inthe POD polymer. Since there can be significant flexing do to arteryflexing or voluntary patient movements integrated contact ends must notbe allowed to extrude from the polymer. A sharp metal object couldseriously harm the patient. This possibility is avoided by integratingthe electrode ends into the suture holes, so even of the polymerdegrades the metal braids forming the contacts will not come loose.

The microstimulator (FIG. 4) itself may contain many innovations, in oneembodiment it is composed of a ceramic such as Alumina/Zirconia® tubewith biocompatible metal fittings such as Titanium/Niobium that arebrazed to the ends of the ceramic tube (FIG. 7). These fittings receivemetal lids that are laser welded creating a hermetic space inside theceramic tube. The ceramic tube may contain one or more Nobel gases andthe electronic hybrid (FIG. 8) in addition to a moisture absorbentmaterial (e.g., “Getter”) to absorb additional moisture for the purposesof hermetic leak testing and absorption of any moisture that maypenetrate the hermetic barrier. The electronic assembly may make contacttwo the two end caps in one implementation by having gold plated springcontacts that press against the gold plated lids with sufficient tomaintain contact even highly vibratory environments.

On the outside of the microstimulator the end caps may make electricalcontact with either the nerve, or the integral POD electrodes, or both.In another embodiment electrodes may be welded to the end caps and theseelectrodes will make contact with either the nerve, or integral PODelectrodes, or both.

The electronic assembly consists of a substrate (FIGS. 10 and 11), oneor more antennae for receiving power, and sending and receiving power toand from outside charging and programming device, replenish able powersource, and an electronic circuit than may autonomously stimulate theneural tissue.

In some variations, the substrate may be constructed from ceramic withpalladium conductors laid down in a thick film process. Circuits aresoldered or attached with conductive epoxy to the traces and in additionthe battery, antennae, and spring contacts are fixated to the substrate.

Antennae may consist of any assembly that can receive power from theexternal electric field. These antennae have certain characteristicssuch a resonant frequency and a quality factor (Q). One implementationof such an antenna is a coil of wire with or without a ferrite core withto form an inductor with a defined inductance (FIGS. 8 and 9). Thisinductor may be coupled with a resonating capacitor and a resistive lossto form the resonant circuit. The frequency may be set to that of theradiated electric field to receive power and data from the externalsource. Data is transmitted back to the source by dynamically loadingthe resonant circuit with real or complex impedance. This can create achange in the load perceived by the external driver of the electricalfield allowing data to be received from the implant. Another embodimentof antennae is a piezoelectric or magneto resistive element. The antennamay also be sized properly to receive sufficient power to charge thereplenishable power source. In the case of planer antennas, multiplanerantennas can be implemented in the implant and/or externally in order tomake the device tolerant to axial rotation (FIG. 9). For instance twoantennae that are rotated 30 degrees (30°) from one another will notachieve the coupling of two antennae on one plane but will maintain adegree of efficiency from any direction.

Electrical contact to the end caps may be made through spring contactsfrom a material such as beryllium copper and gold plated. In combinationwith gold plated end caps, this may form an extremely reliableconnection and isolate the internal hybrid from mechanical and thermalshock. The static tension must be low enough not to warp the hybridboard over the life of the device, making implementation from anon-amorphous material essential. Another embodiment would be to insertthe hybrid in a plastic carrier, and resistance weld connection wiresfrom the end caps to the substrate before the end caps are welded shut.

That replenishable power source can be a battery, capacitor, and ahybrid battery capacitor device with sufficient capacity to power theimplant for extended periods of operation. The power source may berechargeable a number of times sufficiently to support the life of thedevice. In one implementation, a battery made from a lithium solid-statematerial will be used. This material results in a simple charger circuitthat consists of a current limited voltage source that is applied in thepresence of the externally generated electromagnetic field. All thesebattery technologies may be protected by an under voltage cutoff circuitthat completely shuts down device current thus preventing theirreversible chemical changes that occur when a battery is dischargedbelow its minimum voltage. Another characteristic of the power sourcethat may be important is very low leakage or long “shelf-life”.Depending on the battery technology it may be important to record that abattery has migrated to a voltage below its minimum voltage at whichpoint that the battery should not be charged. This is enabled bymeasuring the voltage as soon as power is received on the antenna andshutting off battery charging, thus resulting in a system that cancommunicate with the external system and cannot be used to autonomouslystimulate that patient.

The electrical circuits may consist of a power source charger withprotection circuits, a state machine to control the device, an internalclock, stimulation current sources, protection from an overly intenseelectromagnetic field such as encountered by an over powered transmitteror the dynamic component of a MRI system, protection of external currentgenerators such as those produced by monopolar electro-cautery, finallydemodulation and modulation circuits for receiving and transmittingdata, voltage measurement circuits for monitoring the system and thephysiologic/electrode interface (FIGS. 12 and 13).

In one embodiment all the above circuits are implemented with anintegrated circuit, along with discrete, in another embodiment it wouldconsist of an integrated circuit, discrete components and a separatemicrocontroller that would contain read/write non-volatile memory forcontaining firmware, patient parameters, and required system state. Themicrocontroller may contain other functionality such as analog todigital converters for voltage measurement and digital to analogconverters for driving the stimulus current sources.

Stimulus dosing may benefit from the use of a fairly accurate clock thatgenerates with the time between stimuli, or ticks for a real-time clockthat implements potentially far more complex dosage scenarios. Accurateclocks are typically implemented using piezoelectric crystals but thesecrystals can be large, expensive, and prone to damage. An alternateembodiment involves using a semiconductor junction to generate areference voltage that in turn charges an RC circuit to produce a timereference. Typically these voltage references have significantvariations due to integrated circuit parameters and temperaturevariations. The implant is in a temperature stable environmenteliminating the need for temperature compensation. The wafer to waferand die to die variations can be calibrated at a fixed temperature andscaled to 37 degrees centigrade during manufacturing or can becalibrated during the programming or charging process. The preferredimplementation is to have an accurate time source in the charger,command the implant to produce a specific number of ticks before sendinga message back to the charger. Then the charger would provide to theimplant the actual duration of a tick. Still not being particularaccurate over the period of, for example a year, whenever the charge isconnected it can correct implant time. This model also allows thepatient to move to different time zones without modifying potentiallysalient circadian component of the stimulation.

Power may be extracted from an antenna in the resonant circuit byrectifying using SiGe or appropriately fast low loss diodes, limitingthe peak voltage with a zener diode to the maximum voltage that can betolerated by the integrated circuit and capacitor, and then filtered bya capacitor. Data is transmitted back to the charger/programmer byeither changing the Q of the resonant antenna circuit directly byloading the circuit dynamically.

Telemetry data is encoded on the envelope of the carrier. The carriermay be used as a clock source for the implant to decode the data. Theenvelope may be extracted by a non-linear element (e.g. diode) and thenfiltered to remove the carrier with a low pass filter that has a cutofffrequency between the bit rate and carrier frequency. This envelopesignal may then be sliced by the long or short term average value toproduce binary data and then is decoded.

Back telemetry data may be extracted from the charging antenna bydividing down the incoming differential voltage from the resonantcircuit and demodulating. Demodulation may be performed by extractingthe envelope by a non-linear element (e.g. diode) and then filtered toremove the carrier with a low pass filter that has a cutoff frequencybetween the bit rate and carrier frequency. This envelope signal maythen be sliced by the long or short term average value to produce binarydata and then is decoded.

The output of the slicer is routed to an asynchronous serial port thathas an approximation of the bit clock generated by a laser trimmed andcalibrated oscillator.

The external system that provides charging and programming of the systemconsists of a coil that generates an electromagnetic field of sufficientstrength to penetrate through the patient's body to the location of theimplanted device (FIG. 1). Data is communicated to the implant bymodulating the amplitude of the carrier. Other implementations arepossible where the carrier frequency or phase is modulated. Data isreceived by detecting minute changes caused by load shift keyingimplemented in the implant and demodulating the resultant signal. Thecoil is controlled by a microcontroller in the handheld or worn (e.g.,on the neck) charger that is responsible for charging, programming, andchecking device status. The charging/programmer may be further linkedusing a wired or wireless link to a prescription pad implemented on amobile computing device. The prescription function may be implemented inan LCD screen of the charging device (FIG. 2).

The coil is part of a tuned resonant circuit set to a specificfrequency, or allows shifting frequency to optimize the couplingcoefficient between the external coil and the implant antenna. In thecase of a fixed frequency it will be set to an allocated frequency bandsuch as the International Scientific and Medical Band (125 KHz, 6.78MHz, 13.56 MHz, or 27 MHz). In order to effectively transmit power andstay with allocated frequency bands the Q of the coil may be ratherhigh. A class-E transmitter (FIG. 17) or Class-D (FIG. 19) is wellsuited to drive the coil since it has low parts count and has a veryhigh efficiency. Since the coil is not perfect device and it is highsensitive the dielectric constant of the surround media manycompensations must be made. First the coil may require shielding using aconductive media in close proximity to the coil wires, an electricallyclosed loop cannot be formed or the transmitting coil will be shortedout. Secondly as the transmitting coil is moved towards the skin andimplant the dielectric constant will dramatically shift, this shift willcause a shift in the resonant frequency of the system. Two methods existto ‘re-tune” the circuit: one is to shift the driving frequency alongwith the coil, this requires the implant to be part of the circuit, andthe second method is to have a method to “re-tune” the circuit. This isa more practical approach in the case that the coupling coefficient isless than 2%, which is the typical case for a small and deeply implantedMicrostimulator. The circuit may be dynamically tuned to maximize powertransfer, and/or to minimize side-lobe radiation outside the allocatedfrequency band. Dynamically tuning the loop is typically achieved byusing a variable inductor embedded in a PID controller (FIG. 18)optimized to maximize power transfer or minimize side lobe radiation.The voltages induced across this coil may be in the hundreds of volts,and currents can approach an ampere. The variable inductance techniqueis implemented by inducing a static flux into a series tuning inductormodifying the inductance. This is achieved by winding a primary andsecondary on a ferromagnetic core and inducing a DC current through thesecondary modifying the effective permittivity of the core shifting theprimary inductance. In an embodiment the back telemetry modulation depthon the transmitting coil or power derived to the microstimulator wouldbe measured in the receiving coil and a PID controller would adjust theinductance in the second coil.

Coil power to transmit data can either be shifted by modulating themodulating the ‘collector’ voltage or by gating the carrier on and offto the class-d power amplifier or both. One implementation is todigitally generate the carrier frequency using a phase accumulator (FIG.39) oscillator that allows precise carrier frequency adjustment to aidin tuning the system to maximum the coupling coefficient.

Microstimulator electrode contacts may be designed to loosely couple tothe nerve as not to constrict and thus damage the nerve, but to maintainas much nerve contact as possible. They should be constricted of anaccepted physiologic electrode material such as a platinum iridiumalloy. A rigid or semi-rigid structure allows the POD to be tightenedwithout the possibility of compressing the nerve. In a rigid structure,several sizes may be made available to accommodate the sizes of nervesavailable (FIGS. 3A-3B). A semi-rigid structure allows the contacts tobe bent to size. Different POD sizes are likely required to accommodatethe rigid and semi-rigid structures. Flares and radii may be used toassure that the nerve will not be cut or scraped.

For example, described herein are systems for treating chronicinflammation in a patient. Such a system may include: an implantablemicrostimulator configured for implantation around a cervical portion ofa vagus nerve to modulate inflammation by applying a low duty-cyclestimulation; a charger configured to be worn around the patient's neckand to charge the implantable microstimulator; and an externalcontroller configured to set a dose amplitude and dose interval for themicrostimulator.

In some variations, the system also includes a POD for securing themicrostimulator within the patient. The system may also be configured tocharge the implantable microstimulator for less than about 10 minutesper week, 20 minutes per week, 30 minutes per week, etc.

In general, these systems may be configured for extremely low powerusage, and be adapted for use in modulating inflammation by stimulationof the cervical vagus nerve, because (1) the stimulation is extremelylow duty cycle stimulation (e.g., long off times, brief, relativelylow-intensity on times (stimulation a few times/day for <a few minutes),which allows the use of solid-state batteries and less than on minutecharging cycles following a full day of modulation; (2) themicrostimulators typically use two electrodes and a non-traditional,hermetic feed-through that reduces complexity and size; (3) themicrostimulator may use a single bipolar current source that is targetedto a specific nerve; and (4) ultra-small, ultra-low powermicroprocessors may be used.

In some variations of the system, the charger may be a belt-like loopthat fastens around the patient's neck so that power may be transmittedby the loop to the implant. The external controller may be an electronicprescription pad.

As described in greater detail below, the implantable microstimulatormay comprise a hermetically sealed capsule body having at least twoconductive regions, the capsule body surrounding a resonator, batteryand an electronic assembly sealed within the capsule body, wherein theelectronic assembly is connected to the capsule body by a suspensionconfigured to absorb mechanical shock. In this variation the electronicassembly may comprise power management circuitry configured to receivepower from the resonator to charge the battery, and a microcontrollerconfigured to control stimulation of the vagus nerve from the conductiveregions of the capsule body.

For example, also described herein are systems for treating chronicinflammation in a patient including: an implantable microstimulatorconfigured for implantation around a cervical portion of a vagus nerveto modulate inflammation by applying low duty-cycle stimulation to thevagus nerve; a POD configured to hold the implantable microstimulator incontact with a patient's vagus nerve; a charger configured to be wornaround the patient's neck and to charge the implantable microstimulatorimplanted within the patient's neck region; and an external controllerconfigured to communicate with the microstimulator through the chargerand to thereby set the dose amplitude and dose interval for themicrostimulator, wherein microstimulator is configured to continuouslymodulate inflammation while charging by the charger for less than 10minutes per week. The system may be configured to charge the implantablemicrostimulator for less than about 10 minutes per day, 10 minutes perweek, etc.

Any of the chargers or external controllers described herein may be usedas part of a system.

Also described herein are leadless, implantable microstimulator devicesfor treating chronic inflammation, the device comprising: a hermeticallysealed capsule body; at least two electrically conductive capsuleregions, wherein each region electrically connects to an electrode forapplying stimulation to a vagus nerve; a resonator within the sealedcapsule body; a battery within the sealed capsule body; and anelectronic assembly within the sealed capsule body, wherein theelectronic assembly is connected to the capsule body by a suspensionconfigured to absorb mechanical shock and make electrical contact;wherein the electronic assembly comprises power management circuitryconfigured to receive power from the resonator to charge the battery,and a microcontroller configured to control stimulation of the vagusnerve from the conductive capsule regions.

The capsule body may comprise a ceramic body with hermetically sealedtitanium alloy ends and integral platinum-iridium electrodes attachedthereto.

In some variations, the device further includes an overtemperaturecontrol including a thermister that is configured to shut the devicedown if the operating temperature exceeds a 41° C.

The battery may be a Lithium solid-state battery e.g., (LiPON). Thedevice may also include voltage limiters to limit the amount of powerthat can charge the battery from the resonator. In some variations, thedevice includes load stabilizers to reduce communication errors due topower load fluctuations.

In some variations, the at least two electrically conductive capsuleregions comprise the ends of the capsule body. For example, the at leasttwo electrically conductive capsule regions may be made from a resistivetitanium alloy to reduce magnetic afield absorption.

Any appropriate suspension may be used, such as a clips or springs.

In some variations, the microstimulator device further includes anH-bridge current source with capacitor isolation connecting each of thetwo electrically conductive capsule regions. The microstimulator mayalso include one or more temperature sensor configured to detune theresonator to prevent energy absorption if the temperature exceeds apredetermined value. In some variations the microstimulator includes anovervoltage sensor configured to detune the resonator to prevent energyabsorption. The microstimulator may also include a current limiterconfigured to limit current from the resonator to enable reliablepowerup.

Any appropriate resonator may be used with the microstimulator. Forexample, the resonator may be a coil and capacitor configured toresonate at about 131 KHz+/−2%. The resonator may comprise a ferritecoil wherein the ferromagnetic material is chosen to maximizepermittivity in the operating range and minimize permittivity and energyabsorption from higher frequency sources such as MRI and Diathermydevices.

The electronic assembly of the microstimulator may include telemetrycircuitry configured to detect and demodulate control information fromthe resonator and communicate the control information with themicrocontroller.

Also described herein are leadless, implantable microstimulator devicefor treating chronic inflammation by stimulation of a cervical region ofa vagus nerve that include: a hermetically sealed capsule body havingtwo electrically conductive capsule end regions separated by a centralnon-conductive region, wherein each conductive region is configured toelectrically connect to an electrode for applying stimulation to a vagusnerve; a resonator, battery and electronic assembly within the sealedcapsule body; a suspension connecting the electronic assembly to thecapsule body to absorb mechanical shock; wherein the electronic assemblycomprises power management circuitry configured to receive power fromthe resonator to charge the battery, and a microcontroller configured tocontrol stimulation of the vagus nerve from the conductive capsuleregions.

Also described herein are chargers. For example, a charger deviceconfigured to be worn around a patient's neck for charging amicrostimulator implanted in the patient's neck may include: anenergizer coil configured to fit around the patient's neck; a latchconfigured to releasably secure together two ends of the energizer coilto close the energizer coil and form a solenoid loop around thepatient's neck; and a class-D amplifier driving the solenoid loop andconfigured to create a magnetic field of between about 40 and 100 A/m ata frequency of between about 120 and 140 KHz. The latch may comprise aplurality of pins making electrical connection between the ends of theenergizer coil, the pins configured to maintain a low coil resistanceand high Q.

In some variations, the class-D amplifier comprises a high efficiencyclass-D amplifier. The class-D amplifier may be configured to be drivenat a variable frequency to maximize power transfer. The class-Damplifier output may be driven to optimize the microstimulator powerabsorption by measuring the back-telemetry modulation depth. In somevariations, the class-D amplifier controls temperature and preventstelemetry channel saturation. The class-D amplifier driving the solenoidloop may be configured to create a magnetic field of between about 47-94A/m at a frequency of between about 127-135 KHz.

The charger devices may also include a digitally compensated pwm circuitto modulate the magnetic field strength and tune the power. The deviceof claim 32, further comprising resonators that are adjustable tobetween about 127 KHz to 135 KHz. In some variations, the charger devicealso includes a telemetry system. The telemetry system may include amicroprocessor configured to modulate a transmitter collector voltage tosend data.

Any of the chargers described herein may also include one or moredisplays or indicators (e.g., lights).

Also described herein are charger devices configured to be worn around apatient's neck for charging a microstimulator implanted in the patient'sneck. A charger device may include: a solenoid loop configured to beworn around the patient's neck; a class-D amplifier driving the solenoidloop and configured to create a magnetic field of between about 40 and100 A/m at a frequency of between about 120 and 140 KHz.

Methods of treating chronic inflammation are also described herein,using any (including subsets of) the devices and systems described. Forexample, described herein are methods of treating chronic inflammationin a patient, including the steps of: implanting a microstimulator inthe patient's neck in electrical communication with a cervical region ofthe subject's vagus nerve; and charging and programming the implantedmicrostimulator from a charger worn around the subject's neck. Themethod may also include applying electrical energy to the vagus nerve tomodulate inflammation. The method may also include programming themicrostimulator using an external controller and transmitting controlinformation from the charger.

The step of inserting the microstimulator may include inserting themicrostimulator into a Protection and Orientation device (POD) that atleast partially surrounds the vagus nerve, wherein the POD is configuredto secure the microstimulator in communication with the vagus nerve.

In some variations, the step of inserting the microstimulator comprisesimplanting a microstimulator having a hermetically sealed capsule bodywith at least two electrically conductive capsule regions separated by anon-conductive region and a resonator, battery and electronic assemblywithin the sealed capsule body, and a suspension connecting theelectronic assembly to the capsule body to absorb mechanical shock.

In any of these methods for treatment, the method may include the stepof securing a charging device around the patient's neck. For example,the method may include securing a charging device around the patient'sneck by latching the charging device around the patient's neck to form acomplete solenoid loop.

The step of charging and programming the implanted microstimulator mayinclude emitting a magnetic field of between about 40 and 100 A/m at afrequency of between about 120 and 140 KHz from the charger.

Also described herein are methods of treating chronic inflammation in apatient, the method comprising: implanting a microstimulator in thepatient's neck in electrical communication with a cervical region of thesubject's vagus nerve; stimulating the subject's vagus nerve to modulateinflammation; securing a charging device around the patient's neck; andcharging the implanted microstimulator from a charger worn around thesubject's neck for less than 20 minutes per week by emitting a magneticfield of between about 40 and 100 A/m at a frequency of between about120 and 140 KHz from the charger.

The above summary of the invention is not intended to describe eachillustrated embodiment or every implementation of the present invention,but to highlight certain key features. The figures and the detaileddescription that follow more particularly exemplify these embodimentsand features.

For example, described herein are methods of closed-loop modulation ofthe inflammatory reflex, the method comprising: sensing activity on avagus nerve from a microstimulator implanted around a cervical portionof the vagus nerve; controlling one or more characteristic ofstimulation of the microstimluator based on the sensed activity, whereinthe one or more characteristic of stimulation is selected from the groupconsisting of: duration, intensity, frequency, on-time and off-time; andstimulating the vagus nerve using the microcontroller to apply a lowduty-cycle stimulation to the vagus nerve.

Also described herein are leadless, implantable microstimulator devicefor treating chronic inflammation, the device comprising: a hermeticallysealed capsule body; at least two electrically conductive capsuleregions, wherein each region electrically connects to an electrode forapplying stimulation to a vagus nerve and sensing electrical activityfrom the vagus nerve; a power source within the sealed capsule body; anda controller within the capsule body configured to control theapplication of low duty-cycle stimulation of the vagus nerve usingfeedback from sensed vagus nerve activity in a closed-loop stimulationregime.

In any of the methods of controlling stimulation of the vagus nervebased on sensed vagus nerve activity, the activity may be a neuralresponse on the vagus nerve that is either an evoked potential (e.g.,following or virtually concurrent with stimulation of the vagus nerve)or a neurogram of activity of the vagus nerve.

Any of the methods and devices may include record neural response of thevagus, and may analyze neural activity, including counting spikes andproducing activity histograms, and/or frequency analysis of theactivity.

Any of these methods and devices may include a means to simulate andthen record response to characterize system through disease/conditionspecific neural signatures.

The devices and methods may optimize stimulus based upon neuralactivity. For example, the sensed activity from the vagus nerve may beused to determine the maximum physiologic response at minimal power. Thesensed vagus activity may also be used to determine neural feedback onpatient accommodation to stimulus; accommodation may be avoided byadjusting the timing of stimulation outside of the window ofaccommodation based on feedback. Similarly, the stimulation parameters(e.g., characteristics of stimulation) may be adjusted to preventtachyphylaxis based on the sensed activity or pattern of activitycharacteristic of tachyphylaxis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows one variation of a system for modulating chronicinflammation including a leadless microstimulator (shown connected tothe vagus nerve) and an external charger/controller.

FIG. 1B shows another variation of a system for modulating chronicinflammation, including a microstimulator, charger (“energizer”), andsystem programmer/controller (“prescription pad”).

FIG. 1C shows another variations of a system for modulating chronicinflammation, including a microstimulator, a securing device (POD) forsecuring the leadless stimulator to the nerve, an external charger, asystem programmer/controller (“prescription pad”) and an optionalsurgical tester.

FIG. 1D is a block diagram schematically illustrating themicrostimulator and the charger.

FIG. 2 illustrates one variation of an external systemprogrammer/controller wirelessly connected to a microstimulator.

FIG. 3A shows one variation of a microstimulator in a POD configured tosurround a nerve of the inflammatory reflex. FIG. 3B shows an enlargedview of the microstimulator and POD. FIG. 3C shows another variation ofa microstimulator; FIG. 3D shows the microstimulator of FIG. 3C within aPOD. FIG. 3E shows another variation of the microstimulator.

FIG. 4 shows a schematic diagram of a microstimulator and POD aroundvagus nerve.

FIGS. 5A-5D show end, side perspective, top and side views,respectively, of one variation of a sleeve (“POD”) for securing themicrostimulator around a nerve such as the vagus nerve.

FIGS. 6A-6D show end, side perspective, top and side views,respectively, of one variation of a microstimulator with integralelectrode contacts.

FIG. 7 shows one variations of a ceramic case for a microstimulator withbrazed-on receptacles.

FIG. 8 shows one variation of an electronic assembly and end capswithout spring loaded contacts.

FIG. 9A shows a section though one variation of a microstimulator havingnon-coplanar antennae, and FIG. 9B is a graph illustrating therotational tolerance (efficiency) of the antennae as the angle ischanged.

FIGS. 10A-10C show perspective, top and side views, respectively, of anelectronic assembly of a microstimulator having a solid-state batteryand antenna.

FIGS. 11A-11C show perspective, top and side views, respectively, of anelectronic assembly of a microstimulator having a coin cell battery.

FIGS. 12A and 12B are block schematic circuit diagrams of variations ofmicrostimulators as described herein.

FIGS. 12C and 12D illustrate schematic (circuit) diagrams of a batteryswitch and a voltage supply switch (VSW), respectively.

FIG. 13 is a state diagram showing various operational modes possiblewith a microstimulator as described herein.

FIG. 14 is a block schematic circuit diagram of one variation of animplant hybrid schematic, as described herein.

FIG. 15 is a system schematic for a microstimulator as described in oneexample herein, and FIG. 16 is a high level ASIC schematic of themicrostimulator of FIG. 15.

FIG. 17 is one variation of a Class-E amplifier.

FIG. 18 illustrates one variation of a class E Charger circuit withtuning circuit.

FIG. 19 illustrates one variation of a H-bridge stimulation andmeasurement circuit.

FIG. 20 shows a side view of a patient having an implantedmicrostimulator.

FIGS. 21A-C illustrate one variation of a microstimulator, includingexemplary dimensions.

FIG. 22 shows a schematic of one variation of an ASIC for use in themicrostimulator.

FIGS. 23A and 23B illustrate another variation of a microstimulator asdescribed herein.

FIG. 24A shows a schematic block diagram of the microstimulator of FIG.23A.

FIG. 24B shows a block diagram of the ASIC of FIG. 24A.

FIG. 25A is a graph showing the thermal operation range of amicrostimulator per charging power. FIG. 25B shows a thermal image of amock implant with H=64 A/m.

FIG. 26 shows a discharge curve for one variation of a battery that maybe used with a microstimulator.

FIGS. 27A-D show top, side, side perspective and end views,respectively, of a ferrite resonator that may be used as part of themicrostimulators described herein.

FIG. 28 is a graph of frequency range vs. field strength with andwithout end caps on the microstimulator.

FIG. 29 shows a composite graph of a microstimulator beginning tocharge.

FIG. 30 shows a circuit diagram of a microstimulator including switchcontrol.

FIGS. 31A and 31B illustrate variations of chargers for externallycharging an implanted microstimulator. FIGS. 31C and 31D illustrateanother variation of a charger.

FIG. 32 is a state diagram illustrating the functions of one variationof a charger as described herein.

FIG. 33 is a functional diagram of one variation of a charger asdescribed herein.

FIGS. 34A-34F illustrate different charger displays that may be used.

FIG. 35A shows an exemplary control screen for controlling dosage of thesystem described. FIG. 35B shows an exemplary advanced impedance controlscreen. FIG. 35C shows an exemplary diagnostic screen.

FIGS. 36A and 36B illustrate one variation of a charger for charging andcontrolling a microstimulator implant.

FIG. 37 shows one variation of a coil and magnetic connector assembly.

FIG. 38 is a schematic of the transmission of power between the chargerand a microstimulator.

FIG. 39 shows a functional block diagram of the system operation for onevariation of a charger.

FIG. 40 shows a Class-D amplifier and the back telemetry data detectorfor use with a charger.

FIGS. 41A and 41B illustrates accommodation over time of theimmunological set point. Repeated dosing may alter the immunological setpoint in an adaptive fashion. This adaptation may be subject-specific.FIGS. 41A and 41B both illustrate the effect of multiple 60 second VNSin canine on ex vivo LPS-induced TNF production, averaged (FIG. 41A) andin two exemplary animals (FIG. 41B).

FIGS. 42A and 42B illustrate how chronic VNS may result in tachyphylaxisof the cholinergic anti-inflammatory pathway.

FIGS. 43A and 43B show one variation of the system described herein,which may be configured to sense vagus nerve activity and to use thissensed activity in a closed-loop control (stimulation) method. FIG. 43Billustrates a method of surgically inserting the implantable portion ofthe apparatus shown in FIG. 43A.

FIGS. 44A and 44B illustrates one variation of a microcontroller for usein the implant (referred to as a “hybrid” controller). FIG. 44A shows anenlarged view of the processor/controller portions of the electronics ofFIG. 44B.

FIG. 45 illustrate one variation of a microcontroller that may be usedboth to stimulate the vagus and to sense transmission on the vagus asdescribed herein.

FIG. 46A illustrates a schematic of one variation of an ASIC that may beused with systems/devices including the sensing of vagal activity (e.g.,before/after stimulation), stimulation of the vagus, and control ofstimulation using sensed activity (e.g., analysis of sensed vagalactivity). FIG. 46B schematically illustrates an alternative variationof an ASIC schematic.

FIG. 47 illustrates a method or portion of method for controllingtherapeutic dosing (stimulation) of the vagus to treat inflammationbased on sensed vagus activity.

FIG. 48A shows one example of a neurogram measured from a vagus nerve towhich a microstimulator (in a “pod”) has been coupled, followinginjection of LPS to induce an inflammatory response. Spikes indicateactivity along the vagus nerve. FIG. 48B illustrates another variationof a single channel vagus nerve recording that distinguishes neuralfeatures in the context of an inflammatory challenge. FIG. 48C isanother example of a single-channel vagus nerve recording showing adistinction between low frequency spike characteristics following LPSadministration. FIG. 48D illustrates low frequency spike having anunderlying vagal tone of approximately 35-55 Hz in conjunction with ECGrecording. Any of the neurograms shown may be detecting using themicrostimulators described herein and such neurograms may be used tomodify stimulation as described herein and/or for training the system tomodify/control stimulation.

FIGS. 49A and 49B illustrates variations of microstimulator systems,including canine and rodent devices/systems.

FIG. 50 illustrates one example of a micro stimulator that may be usedto record biological information (e.g., neurogram) that may be used tomodify timing, pattern and/or intensity of stimulation.

FIG. 51 is an ENG (neurogram) of a rat vagus nerve measured using animplanted device such as the device shown in FIG. 49B.

FIG. 52 is an example of an ENG and ECG following the addition of LPSwithout vagal nerve stimulation.

FIG. 53A illustrates a spectral analysis of an ENG (“ENG 1”). FIG. 53Bis a spectrogram of an ENG from 0-65 Hz, showing a large increase in the25-45 Hz power range shortly following LPS injection.

FIG. 54A illustrates a spectral analysis of an ENG (“ENG 2”). FIGS. 54Band C is a continuous spectrogram of an ENG 0-65 Hz showing a speciallypatterned power increase between ˜40-50 Hz following VNS, as well as theperturbation and dampening in the power increase following vagal nervestimulation subsequent to LPS injection. FIG. 54D shows ENG and ECGtracings highlighting the baseline epoch. FIG. 54E are ENG and ECGtracings highlighting the epoch post VNS, but before LPS injection. FIG.54F are ENG and ECG tracings highlighting the epoch post LPS. FIG. 54Gis shows a baseline recording. FIG. 54H is similar to FIG. 54F but showsthe trace post VNS, but before LPS injection. FIG. 54I shows the tracepost LPS injection.

DETAILED DESCRIPTION

Systems for electrically stimulating one or more nerves to treat chronicinflammation may include an implantable, wireless microstimulator suchas those described herein and an external charging device (which may bereferred to as a charging wand, charger, or energizer). In somevariations the system also includes a controller such as a “prescriptionpad” that helps control and regulate the dose delivered by the system.The microstimulator may be secured in position using a securing device(which may be referred to as a “POD”) to hold the microstimulator inposition around or adjacent to a nerve. These microstimulators aredesigned and adapted for treatment of chronic inflammation, and may beconfigured specifically for such use. Thus, an implantablemicrostimulator may be small, and adapted for the low duty-cyclestimulation to modulate inflammation. For example, the implantablemicrostimulator may hold a relatively small amount of power over weeksor even months and discharge it at a rate sufficient to modulate theanti-inflammatory pathway without significantly depressing heart rate ortriggering any number of unwanted effects from the vagus nerve or otherneural connections. Any of the nerves of the inflammatory reflex,including the vagus nerve, may be treated as described herein using thesystems described.

For example, FIG. 1 illustrates one variation of a system for treatingchronic inflammation that includes a microstimulator contained in PODthat is mounted on cervical vagus nerve and charged a programmed by anexternal charger/programmer unit. This variation of a system includes amicrostimulator 103 that has been implanted to contact the vagus nerveas shown. The implant may be programmed, controlled and/or charged by acharger/controller 105 device. In this variation the charger/controlleris a loop with a wand region.

FIG. 1B shows another variation of a system for treating chronicinflammation that also includes an implantable microstimulator 103(shown inserted into a POD to hold it in position relative to a nerve)and a charging device (“energizer” 105) configured as a collar to beworn around the subject's neck and charge the implant. Optionally, thesystem may include a prescription pad 107 which may be a separatededicated device or part of a mobile or other handheld device (e.g., anapplication to run on a handheld device).

FIG. 1C shows another variation of a system for treating chronicinflammation. The systems described herein may also be referred to assystems for the neural stimulation of the cholinergic anti-inflammatorypathway (NCAP). These systems may be configured as chronic implantablesystems. In some variations, the systems are configured to treat acutely(e.g., acute may 8 hours or less), sub-acutely (expected to occur forfewer than 30 days), or chronically (expected to occur for more than 30days).

In general, the systems described herein may be configured to applyelectrical stimulation at a minimum level necessary to modulate theinflammatory reflex (e.g., modulating cytokine release) characterized bythe Chronaxie and rheobase. Chronaxie typically refers to the minimumtime over which an electric current double the strength of the rheobaseneeds to be applied in order to stimulate the neuron. Rheobase is theminimal electrical current of infinite duration that results in anaction potential. As used herein, cytokines refer to a category ofsignaling proteins and glycoproteins that, like hormones andneurotransmitters, are used extensively in cellular communication.

The NCAP Systems described herein are typically intended for thetreatment of chronic inflammation through the use of implanted neuralstimulation devices (microstimulators) to affect the Neural Stimulationof the Cholinergic Anti-inflammatory Pathway (NCAP) as a potentialtherapeutic intervention for rheumatologic and otherinflammation-mediated diseases and disorders. Neurostimulation of theCholinergic Anti-inflammatory Pathway (NCAP) has been shown to modulateinflammation. Thus, the treatment and management of symptoms manifestedfrom the onset of disease (e.g., inflammatory disease) is based upon theconcept of modulating the Cholinergic Anti-inflammatory Pathway. TheNCAP pathway normally maintains precise restraint of the circulatingimmune cells. As used herein, the CAP is a reflex that utilizescholinergic nerve signals traveling via the Vagus nerve between thebrain, chemoreceptors, and the reticuloendothelial system (e.g., spleen,liver). Local release of pro-inflammatory cytokines (e.g., tumornecrosis factor or TNF) from resident immune cells is inhibited by theefferent, or indirectly by afferent vagus nerve signals. NCAP causesimportant changes in the function and microenvironment of the spleen,liver and other reticuloendothelial organs. Leukocytes which circulatesystemically become “educated” as they traverse the liver and spleen arethereby functionally down regulated by the affected environment of thereticuloendothelial system. This effect can potentially occur even inthe absence of an inflammatory condition.

Under this model, remote inflammation is then dampened by down-regulatedcytokine levels. Stimulation of the vagus nerve with a specific regimentof electrical pulses regulates production of pro-inflammatory cytokines.In-turn, the down regulation of these cytokines may reduce localizedinflammation in joints and other organs of patients with autoimmune andinflammatory disorders.

The NCAP System includes a neurostimulator that may trigger the CAP bystimulating the cervical vagus nerve. The NCAP System issues a timedburst of current controlled pulses with sufficient amplitude to triggerthe CAP at a particular interval. These two parameters, Dose Amplitudeand Dose Interval, may be used by a clinician to adjust the device. Forexample, the clinician may set the Dose Amplitude by modifying thecurrent level. The Dose Interval may be set by changing the durationbetween Doses (e.g. 12, 24, 48 hours).

In some variations, dose amplitude may be set to within the TherapyWindow. The Therapy window is defined as the lower limit of currentnecessary to trigger the CAP, and the upper limit is the level at whichthe Patient feels uncomfortable. The lower limit is called the Threshold(T), and the uncomfortable level is called Upper Comfort Level (UCL).

Dose Amplitude thresholds are nonlinearly dependent upon Current (I),Pulse width (PW), Pulse Frequency (PF), and Burst Duration (BD)Amplitude is primarily set by charge (Q), that is Current (I)×Pulsewidth (PW). In neurostimulation applications current has the most linearrelationship when determining thresholds and working within the therapywindow. Therefore, the clinician may modify Dose Amplitude by modifyingcurrent. The other parameters are held to experimentally determineddefaults. Pulse width is selected to be narrow enough to minimize musclerecruitment and wide enough to be well above the chronaxie of thetargeted neurons. Stimulus duration and pulse frequency was determinedexperimentally in Preclinical work.

Dose Interval may be specific for particular diseases and the intensityof diseases experienced by a patient. Our initial research has indicatedthat the cervical portion of the vagus nerve may be an ideal anatomiclocation for delivery of stimulation. The nerve runs through the carotidsheath parallel to the internal jugular vein and carotid artery. At thislocation, excitation thresholds for the vagus are low, and the nerve issurgically accessible. We have not found any significant difference inbiomarker modulation (e.g., modulation of cytokines) between right andleft. Even though the right vagus is thought to have lower thresholdsthan the left in triggering cardiac dysrythmias, the thresholdsnecessary for NCAP are much lower than those expected to cause suchdysrythmias Therefore a device delivering NCAP can safely be applied toeither the right or left vagus.

We have also found, surprisingly, that the Therapy Window is maximizedon the cervical vagus through the use of a bipolar cuff electrodedesign. Key parameters of the cuff may be: spacing and shielding of thecontacts. For example, the contact points or bands may be spaced 1-2diameters of the vagus nerve apart, and it may be helpful to shieldcurrent from these contacts from other nearby structures susceptible toinadvertent triggering. The cuff may be further optimized by using bandswhich are as long and wide as possible to reduce neurostimulator powerrequirements.

Thus, any variations of the systems described herein (e.g., the NCAPsystem) may be implemented with a Cuff, Lead and Implantable PulseGeneration (IPG), or a Leadless Cuff. The preferred implementation is aleadless cuff implemented by a microstimulator with integral electrodecontacts in intimate contact with the nerve and contained within aProtection and Orientation Device (POD). This is illustrated in FIGS. 3Aand 3B. The POD 301 may form a current shield, hold the microstimulatorinto place against the vagus nerve, and extend the microstimulatorintegral contacts with integral contacts in the POD itself. The POD istypically a polymer shell that encapsulates a microstimulator implantand that allows a nerve to run through the interior against the shellwall parallel to the length of the microstimulator implant. Within theshell of the POD, the microstimulator implant remains fixed against theVagus nerve so the electrodes remain in contact with the nerve. The PODanchors the implant in place and prevents the implant from rotating orseparating from the nerve, as well as maintaining contact between theelectrodes and the nerve and preserving the orientation as necessary forefficient external charging of the microstimulator battery.

Referring back to FIG. 1C, the system may include an implantablemicrostimulator contained in a POD, a Patient Charger, and aprescription pad that may be used by the clinician to set dosageparameters for the patient. This system may evaluate the efficacy,safety, and usability of an NCAP technology for chronic treatment ofclinical patients. The system can employ a Prescription Pad (externalcontroller) that may include the range of treatment options.

As described in more detail in U.S. patent publication no.US-2011-0054569 (titled “PRESCRIPTION PAD FOR TREATMENT OF INFLAMMATORYDISORDERS”), previously incorporated by reference in its entirety, thePrescription Pad may incorporate workflows in a simplified interface andprovide data collection facilities that can be transferred to anexternal database utilizing commercially robust and compliant methodsand procedures. In use, the system may be recommended for use by aclinician after assessing a patient; the clinician may determine thattreatment of chronic inflammation is warranted. The clinician may thenrefer the patient to an interventional doctor to implant themicrostimulator. Thereafter then clinician (or another clinician) maymonitor the patient and adjust the device via a wireless programmer(e.g. prescription pad). The clinician may be trained in the diagnosisand treatment procedures for autoimmune and inflammatory disorders; theinterventional placement of the system may be performed by a surgeontrained in the implantation of active neurostimulation devices, with asufficient depth of knowledge and experience regarding cervical andvagal anatomy, experienced in performing surgical dissections in andaround the carotid sheath.

The system may output signals, including diagnostics, historicaltreatment schedules, or the like. The clinician may adjust the deviceduring flares and/or during routine visits. Examples of implantation ofthe microstimulator were provided in U.S. patent publication no.US-2011-0054569. For example, the implant may be inserted by making anincision in the skin (e.g., ≈3 cm) along Lange's crease between theFacial Vein and the Omohyoid muscle, reflecting the Sternocleidomastoidand gaining access to the carotid sheath. The IJV may be displaced, andthe vagus may be dissected from the carotid wall (≤2 cm). A sizing toolmay be used to measure the vagus, and an appropriate Microstimulator andPOD Kit (small, medium, large) may be selected. The POD may then beinserted under nerve with the POD opening facing the surgeon, so thatthe microstimulator can be inserted inside POD so that themicrostimulator contacts capture the vagus. The POD may then be suturedshut. In some variations a Surgical Tester may be used to activate themicrostimulator and perform system integrity and impedance checks, andshut the microstimulator off, during or after the implantation. In othervariations the surgical tester may be unnecessary, as described ingreater detail below.

A physician may use the Patient Charger to activate the microstimulator,perform integrity checks, and assure sufficient battery reserve exists.Electrodes may be conditioned with sub-threshold current and impedancesmay be measured. A Physician may charge the microstimulator. In somevariations a separate charger (e.g., an “energizer”) may be used by thepatient directly, separate from the controller the physician may use.Alternatively, the patient controller may include controls for operationby a physician; the system may lock out non-physicians (e.g., those nothaving a key, code, or other security pass) from operating or modifyingthe controls.

In general, a physician may establish safe dosage levels. The physicianmay slowly increment current level to establish a maximum limit (UpperComfort Limit). This current level may be used to set the Dosage Level.The exact procedure may be determined during this clinical phase.

The Physician may also specify dosing parameters that specify dosagelevels and dosage intervals. The device may contain several concurrentdosing programs which may be used to acclimate the patient to stimulus,gradually increase dosage until efficacy is achieved, resettachyphylaxis, or deal with unique patient situations.

As mentioned, a patient may use the Patient Charger to replenish themicrostimulator battery at necessary times (e.g., every day, every week,etc.). A clinician may also work with the patient to setup a schedulebased upon the patient's stimulation needs and lifestyle. In somevariations, the microstimulator battery charging is achieved byexpanding the Patient Charger loop, putting the loop over the head, andclosing the handle to close the loop, which may position the chargersufficiently near the implanted device. Charging may start automaticallyor the user (patient or physician) can push a charge button. The patientmay watch the progress on the Patient Charger and may be signaled whencharging is complete. The length of the charge may depend primarily upondosage level. The more often a patient charges, the shorter the chargetime may be.

The charger and/or implant may include a clock, and in some variationsthe patient may set the time zone on the Patient Charger to reflecthis/her location. The Patient Charger may update the microstimulatortime parameters while charging. This may enable the patient to adjustfor travel related time zone changes or daylight savings timeadjustments. Because stimulation may be perceptible (felt by thepatient), it may be important that the patient receive the stimulationat the same time(s) every day.

If the patient does not charge frequently enough, the system mayautomatically cease treatment when about 3 months of standby batteryremains. Once treatment stops the patient must visit their physician torestart treatment, to avoid damage to the implant requiringreimplantation.

In general, the microstimulator and POD can be suitable for chronictreatment with a design life of 10 years or more. The battery maysupport a 20 year life. Microstimulator battery charging intervals maybe dependent on patient dose settings, however, as described in greaterdetail below, the system may be configured to conserve power andtherefore minimize charging intervals and/or times, greatly enhancingpatient comfort and compliance.

The microstimulator and POD may be packaged into kits. Any of thesystems described herein may also include a surgical kit with the itemsnecessary for the implantation of Microstimulator and POD. This does notprevent the surgeon, during a revision, from using the existing POD andonly replacing the microstimulator. System kits may be available forsmall, medium, and large vagus nerves. A vagus nerve sizing kit may beavailable to determine which kit to use. In some variations themicrostimulator and POD have a loose fit such the lumen of the deviceand the widest part of the nerve has a loose fit without constrainingblood flow, and allowing axial flexibility and both compressive andtensile forces on the device without damaging the nerve. For example,the POD may encapsulate the microstimulator so current leakage may occurthrough vagus nerve access ports. All other sources of current leakagemay be <25 uA when POD is sutured shut. The microstimulator may have aslot for the vagus nerve. This slot may have three sizes (approximatelysmall, medium, large) for vagus nerves of approximately (e.g., +/−5%,10%, 20%, 30%, 40%, 50%): 2 w×1.5 h; 3 w×2 h; 4 w×3 h (mm).

Implantable components of the microstimulator and POD and components aretypically applied within the sterile barrier during the interventionalprocedure and may be supplied sterile. Sterilization method may beEthylene Oxide (EO).

In some variations, the POD may be secured by 1-3 sutures and mayinclude a marker to easily allow surgeon to match suture holesminimizing failure. The POD may be configured so that over-tighteningthe sutures does not cause vagal devascularization. The microstimulatorand POD cross sectional area may not exceed 60 mm2 including the largestnerve model. The volume including the largest nerve model may be lessthan 1.5 cc.

Because rotation around the axis and movement up and down on the vagusnerve may occur during the healing period. The Patient Charger may allowaccommodation of this movement.

In some variations, the microstimulator may have a bipolar stimulationcurrent source that produce as stimulation dose with the characteristicsshown in table 1, below. In some variation, the system may be configuredto allow adjustment of the “Advanced Parameters” listed below; in somevariations the parameters may be configured so that they arepredetermined or pre-set. In some variations, the Advanced Parametersare not adjustable (or shown) to the clinician. All parameters listed inTable 1 are ±5% unless specified otherwise.

TABLE 1 Microstimulator parameters Property Value Default Dosage 0-5,000μA in 25 μA steps 0 Amplitude (DA) Intervals Minute, Hour, Day, Week,Day Month Number of N = 60 Maximum 1 Doses per Interval AdvancedParameters Pulse width 100-1,000 μS in 50 μS 200 Range (PW) incrementsStimulus 1-1000 seconds per dose 60 Duration (SD) Pulse 1-50 Hz 10Frequency (PF) Stimulus ±3.3 or ±5.5 ± 1 Volts Automatically set Voltage(SV) by software Constant ±15% over supported range Current of loadimpedances (200- Output 2000 Ω) Specific Dose Set a specific timebetween Driven by default Time 12:00 am-12:00 am in one table (TBD)minute increments for each Dose Issue Number of 4 maximum 1 SequentialDosing Programs

The Dosage Interval is defined as the time between Stimulation Doses. Insome variations, to support more advanced dosing scenarios, up to four‘programs’ can run sequentially. Each program has a start date and timeand will run until the next program starts. Dosing may be suspendedwhile the Prescription Pad is in Programming Mode. Dosing may typicallycontinue as normal while charging. Programs may be loaded into one offour available slots and can be tested before they start running Low,Typical, and High Dose schedules may be provided. A continuousapplication schedule may be available by charging every day, or at someother predetermined charging interval. For example, Table 2 illustratesexemplary properties for low, typical and high dose charging intervals:

TABLE 2 low typical and high dose charging intervals Property Value LowDose Days 30 days max: 250 μA, 200 μS, 60 s, 24 hr, Charge Interval 10Hz, ±3.3 V Typical Dose 30 days max: 1,000 μA, 200 μS, 120 s, 24 ChargeInterval hr, 10 Hz, ±3.3 V High Dose Charge 3.5 days max: 5,000 μA, 500μS, 240 s, Interval 24 hr, 20 Hz, ±5.5 V,

The system may also be configured to limit the leakage and maximum andminimum charge densities, to protect the patient, as shown in Table 3:

TABLE 3 safety parameters Property Value Hardware DC Leakage <50 nAProtection Maximum Charge 30 μC/cm²/phase Density Maximum Current 30mA/cm² Density

In some variations, the system may also be configured to allow thefollowing functions (listed in Table 4, below):

TABLE 4 Additional functions of the microstimulator and/or controller(s)Function Details Charging Replenish Battery Battery Check Determinecharge level System Check Self Diagnostics Relative Temperaturedifference from Temperature baseline Program Read/Write/Modify a dosageManagement parameter programs Program Transfer entire dosage parameterUp/Download programs Electrode Bipolar Impedance (Complex) ImpedancesSignal Strength Strength of the charging signal to assist the patient inaligning the external Charge to the implanted Microstimulator. PatientParameters Patient Information Patient History Limited programming andexception data Implant Time/Zone GMT + Time zone, 1 minute resolution,updated by Charger each charge session Firmware Reload Boot loaderallows complete firmware reload Emergency Stop Disable dosing programsand complete power down system until Prescription Pad connected

As mentioned above, in some variations, the system may record functionof the microstimulator (e.g., a limited patient history). For example,the system may record: date and time that each program that is startedand the associated program parameters; power down events dueundercharging; hardware or software exceptions; emergency power downevents; compliance events with associated impedance measurement; etc. Insome variations, at least the last 50 events may be preserved in acircular buffer. Any of the systems describe herein may be approved forMRI usage at 3 Tesla (e.g., the torque will be less than a maximumthreshold, the temperature rise may be less than 4° C., and the blackoutarea may be less than a maximum threshold volume. In some variations,the microstimulator and POD may be configured to withstand monopolarelectrocautery.

The Patient Charger (including the energizer variations) typically fitsover a patient's head to charge the implants in the patient's neck. Asdescribed in greater detail below, the Patient Charger may support neckcircumferences ranging between 28-48 cm and head circumferences of up to72 cm. The implant and the charger may further be configured so thatthey orientation of the charger and implant may allow sufficienttolerance to permit charging when worn by the user in a number ofpositions, without requiring substantial repositioning. The PatientCharger may provide functionality that can be accessed though aconnected Prescription Pad or other external controller. For example,Table 5 below lists some function elements that may be accessed by aprescription pad in conjunction with a charger:

TABLE 5 functions that may be performed by prescription pad and chargerPrescription Pad connected to Function Charger Charger Alone Charging YY Battery Check Y Y System Check Y Y Absolute device Y Used for thermalTemperature safety purposes only Program Y N Management Program Y NUp/Download Electrode Y OK Check Only Impedances Signal Strength Y YPatient Parameters Y N Patient History Y N Implant Y (time zone not Y(synced to Time/Zone/Date changed Charger and changed) by patient)Firmware Reload Y N Emergency Stop Y Y (special sequence)

In general, a charger (which may be used by a patient directly) mayinclude a recharge reminder alarm (audio and/or visual) that will remindthe patient to charger on a daily, weekly, or monthly frequency. ThePatient Charger may be charged through a Wall Adapter plug alone or inconjunction with a Charging Dock. The Patient Charger may clearlyindicate that it is charging.

In some variations, the Patient Charger firmware will be versioncontrolled and may be updated with Prescription Pad software in thefield, or can be updated in the factory. For example, the PrescriptionPad software may be controlled and may be updated in the field by theone or more web applications, a USB Dongle, a CD, etc. In somevariations, the Prescription Pad may identify the microstimulatorthrough a unique electronic ID electronically available in themicrostimulator. The ID may be linked to a serial number that isembossed in the case. However, the Patient Charger may not requireknowledge of this ID to charge the device.

In determining a maximum neck diameter for use with the chargersdescribed herein a study measuring Neck Circumference for men (N=460)(above) and women (N=519) (below) against BMI was used. See, e.g.,Liubov Ben-Noun, et. al. Neck Circumference as a Simple ScreeningMeasure for Identifying Overweight and Obese Patients, Obesity Research(2001) 9, 470-477. Further, maximum head diameter was determined from ananalysis of other studies (such as K M D Bushby, et al, Centiles foradult head circumference, Archives of Disease in Childhood 1992; 67:1286-1287).

Based on this analysis, the sizing and placement of the charger aroundthe patient's neck was estimated. For example, see FIG. 20. In thisfigure, a side view of a patient with an implanted microstimulator isshown in relation to the subject's neck and shoulders. The “offset” isillustrated as the maximum allowable offset between center of PatientCharging Loop and center of implant, θ pm is the maximum angulardeviation from the Patient Charging Loops normal vector, and H=PatientCharging Loop Height. These variables were used to determine thenecessary properties for the functionality of the charger relative to atypical implanted insert.

In some variations, the Prescription Pad may be configured to handlemultiple patients and may index their data by the microstimulator SerialNumber. For example, a Prescription Pad may handle up to 100,000patients and 10,000 records per patient, and may store the data in itslocal memory and may be backed up on an external database. In somevariations, during each charging session, accumulated even log contentswill be uploaded to the Patient Charger for later transfer toPrescription Pad. The data may or may not be cleared from themicrostimulator. For example, FIG. 2 shows the addition of aprescription pad wirelessly connected to the charger/programmer

Microstimulator

The microstimulators described herein are configured for implantationand stimulation of the cholinergic anti-inflammatory pathway, andespecially the vagus nerve. In particular the microstimulators describedherein are configured for implantation in the cervical region of thevagus nerve to provide extremely low duty-cycle stimulation sufficientto modulate inflammation. These microstimulators may be adapted for thispurpose by including one or more of the following characteristics, whichare described in greater detail herein: the conductive capsule ends ofthe microstimulator may be routed to separate electrodes; the conductivecapsule ends may be made from resistive titanium alloy to reducemagnetic field absorption; the electrodes may be positioned in a polymersaddle; the device includes a suspension (e.g., components may besuspended by metal clips) to safeguard the electronics from mechanicalforces and shock; the device may include an H-bridge current source withcapacitor isolation on both leads; the device may include a built intemperature sensor that stops energy absorption from any RF source bydetuning the resonator; the device may include a built-in overvoltagesensor to stop energy absorption from any RF source by detuningresonator; the system may include DACs that are used to calibratesilicon for battery charging and protection; the system may include DACsthat are used to calibrate silicon for precision timing rather thanrelying on crystal oscillator; the system may include a load stabilizerthat maintains constant load so that inductive system can communicateefficiently; the system may include current limiters to prevent acurrent rush so that the microstimulator will power up smoothly fromresonator power source; the system may extract a clock from carrier ORfrom internal clock; the device may use an ultra-low power accurate RCoscillator that uses stable temperature in body, DAC calibration, andclock adjustment during charging process; the device may use a solidstate LIPON battery that allows fast recharge, supports many cycles,cannot explode, and is easy to charge with constant voltage; and thedevice may include a resonator that uses low frequency material designednot to absorb energy by high frequency sources such as MRI and Diathermydevices.

Many of these improvements permit the device to have an extremely smallfootprint and power consumption, while still effectively modulating thevagus nerve.

As mentioned above, some of the device variations described herein maybe used with a POD to secure the implant (e.g., the leadless/wirelessmicrostimulator implant) in position within the cervical region of thevagus nerve so that the device may be programmed and recharged by thecharger/programmer (e.g., “energizer”). For example, FIG. 4 shows aschematic diagram of a POD containing a microstimulator. The crosssection in FIG. 4 shows the ceramic tube containing electronic assemblythat includes the hybrid, battery and coil. The rigid or semi-rigidcontacts are mounted on the tube and surround the oval vagus nerve. ThePOD surrounds the entire device and includes a metal conductor thatmakes electrical contact with the microstimulator contacts andelectrically surrounds the nerve.

FIG. 3A is a perspective drawing of the Pod containing themicrostimulator. Sutures (not shown) are intended to be bridged acrossone to three sets of holes. Electrodes integrated into the pod are notshown but would extend as bands originating and ending on the two outerpairs of suture holes.

FIGS. 5A-D show views of one variation of a POD without an insertedmicrostimulator. The keying can be seen in the saw tooth pattern so thatthe surgeon will assure that the device does not twist the suture holesare reinforced with Dacron material embedded in the polymer. The tunnelthat the nerve takes is as conformal as possible. Several sizes may berequired in order to minimize current leakage and limit fibrous tissuein-growth. FIGS. 6A-D show another variation of a microstimulator fromseveral angles. FIGS. 7-11C illustrate different variations ofcomponents of microstimulators as described herein. For example, FIG. 7shows a ceramic tube forming the outer region of the microstimulatorhousing with end fixtures allowing the titanium caps to be weldedsealing the unit. FIG. 8 shows the electronic assembly with the endcaps. The antenna is on top of the hybrid and the battery is below thehybrid. Spring loaded contacts are on the edge of the board (not shown)will press against and make electrical contact with the end caps.

As described above, the microstimulators described herein are configuredto be used with a charger to be worn on a subject's neck. Thus, themicrostimulator must be configured to allow charging when wearing thedevice. FIG. 9A shows a cross section of one variation of amicrostimulator showing detail of an inductive antenna wound in twoplanes to increase the rotational tolerance of the device. The graph inFIG. 9B below shows the relative efficiency when the angle between thetwo planes is changed.

FIGS. 10A-10C show detail of the hybrid microstimulator, in particularshowing the integrated circuit and MCU, in addition to the discretecomponents. The ends of the board have contacts for the spring loadedcontacts described above. As shown, the DC protection capacitors aremounted as close as possible to the contacts to avoid other possible DCleakage paths that could develop on the board. FIGS. 11A-C are similarto FIGS. 10A-C except they show a coin cell rather than a then a thinsolid state battery shown in FIGS. 10A-C.

FIGS. 12-19 are circuit diagrams illustrating one variations of amicrostimulator system having many of the properties described above,and in particular limits protecting operation and powering of themicrostimulator. For example, FIG. 12A is a block diagram of the circuitshowing overall function of a microstimulator. Electromagnetic energy ispicked up by the resonant circuit formed by the inductor and capacitor.A diode rectifies the energy and another capacitor filters the powersupply. A limiter provides the function of limiting the voltage andcurrent to the battery cell that is being charged. J1 is removed for aprimary cell system that does not require recharging, for a rechargeablesystem J1 is always present. S1 is normally connected, and is onlydisconnected when the battery runs below a level where it is in dangerof being damaged. If S1 gets disconnected it is reconnected after thebattery is under charge. The real-time-clock (RTC) is normally connectedand tracking time. Once charging is complete and the MCU has completedwork, it sets up the RTC for a wakeup call. A wakeup call consists ofthe RTC closing S2 powers up the MCU. The MCU keeps S2 closed until itsbusiness is complete. The MCU gets data from the demodulator using theUART to convert the serial asynchronous data to parallel bytes. The UARTis also used to modulate the load on the resonant circuit and the datais picked up by the programmer and charger. The MCU stimulates thepatient by using current sources. The battery voltage may not be highenough to overcome the electrode impedances, in this case the Voltagemultiplier is enabled to increase the stimulation voltage. The bipolarcurrent sources are connected in an H-bridge formation (see FIG. 19) andthe output capacitors allow a positive voltage to be swung negativelyyielding peak to peak voltage swings double the stimulation voltage.

FIG. 14 shows the implant hybrid schematic. The Micro custom integratedcircuit along with the MCU performs the functions described in FIG. 12A.D1 and C3 rectify power; D3 is a zener diode that prevents over voltageconditions. D2 demodulates data. R11 sets the scaling from the voltageDAC to the current sinks. C7 and C8 form the H-bridge swing capacitorsand provide DC protection. BT1 is the power source and the remainingcapacitors are used to stabilize power supply voltages and multiple thevoltages.

FIG. 17 is a Class-E amplifier as used in the Charging circuit. Lt isthe transmitting antennae, Lt and Ct form the resonant circuit and Rs isused to reduce Q to the desired value. Ct is adjusted to obtain theproper frequency. Cc compensates for the MOSFET capacitance; Lc forms aconstant current source.

FIG. 18 utilizes a class-D or class-E amplifier in a charging circuitwith a second series variable inductor. A PID controller uses thevoltage across the two series inductors to control the carrier frequencyand the inductance through a DC voltage that in turn varies the staticflux in the variable inductor.

FIG. 19 is an example of two current sinks implementing an H-bridgebipolar current source. Q4 A&B implements a current mirror that iscontrolled by a DAC fed through R11. A voltage induced on R11 isconverted to a current and is pulled through C6 while simultaneously Q2A is opened allowing current to flow through C7 across an externalphysiologic load not shown. Q4 and Q2B are shut off. Then the Q5 A&Bcurrent mirror is turned on through R12 while Q2 A is turned on and thecurrent is reversed through C6 and C7 across the physiological loadcompleting the bipolar pulse. The R8∥R9 and R7∥R10 form voltage dividersthat are measured by the differential amplifier (U7). Thus when aspecified current is commanded the voltage produced on the differentialamplifier indicates the electrode impedance. Also when the voltage getsclose to the capability of the supply the system is said to be ‘out ofthe compliance’ and the current is not guaranteed. At this point thesystem can increase the charge by increasing the pulse width orincreasing the voltage through the voltage multiplier. R8∥R9 and R7∥R10also keep C6 and C7 discharged since a charge imbalance will develop dueto the mismatch between the Q4 and Q5 current sources.

In many variations, the microstimulators described herein are tunableelectrical nerve stimulators configured to deliver modulated electricalstimulus to the vagus nerve of the patient for treatment of inflammatoryand autoimmune disorders. The microstimulator, in conjunction with thePOD, is intended to perform as a chronic stimulating unit that generatesoutput pulses with defined electrical characteristics to the vagus nerveof a patient. The stimulator is intended for chronic use and may becapable of executing patient specific programs with varying parametersin order to treat a wide array of diseases with differing severitylevels.

In some variations, including those described above, the microstimulatorconsists of a ceramic body with hermetically sealed titanium-niobiumends and integral platinum-iridium electrodes attached. Themicrostimulator may be designed to fit within a POD 309, as shown inFIGS. 3A and 3D. As described above, the POD is a biocompatible polymerwith integrated electrodes that may help the microstimulator to functionas a leadless cuff electrode. In some variations, such as the variationshown in FIG. 3E, contained within the hermetic space of themicrostimulator 301 is an electronic assembly that contains arechargeable battery 321, solenoid antenna 323, hybrid circuit 325 andelectrode contacts (Ti Alloy braze ring and end cap) 327 at each end tomake contact with the titanium/platinum case ends.

In general, the microstimulator is designed to be implanted within deeptissue, so that it can be recharged and controlled using an external(e.g., transcutaneous) inductive link through a charger encircling theimplant outside the body. One advantage to the microstimulatorsconfigured as described herein (including the extremely low duty-cycleof the device) is the low energy requirements of these devices,particularly as compared to prior art devices. For example, Table 6,below illustrates exemplary charging and use profiles for low, typicaland maximally used implants. In general, the daily charging duration forlow and average patients may be less than 2 minutes/day, and for Maximumpatients less than 10 minutes per day.

TABLE 6 Use and charge profiles Full Charge Frequency Patient DischargeDaily Weekly Monthly Low 53 days 0.4 min 2.6 min 11.3 min Typical 50days 0.4 min 2.8 min 12.0 min Maximum  5 days 3.7 min NA NA

FIG. 12B shows another example of one variation of an implant includingthe following features: resonant antenna circuit (L/Cr) to receiveelectromagnetic energy from the external Patient Charger; rectifier andfilter (D/Cf) to convert energy from AC to DC; voltage limiter (Z) toprotect the circuitry; a secondary battery and brown-out capacitor(B/Cb) to store energy and filter power-on demand current spikes createdby high impedance of battery; charger circuit to regulate chargingvoltage and limit current if the battery fails; real-time-clock (RTC)tracks time and provides wake-up alarms to MCU is always powered if thebattery is connected; a communications system to receive amplitudemodulated data between the patient charger and microstimulator(Mod/Demod/UART); a charge pump to boost the voltage when required todrive electrodes; a Bipolar current source to drive the electrodes witha constant current biphasic waveform; microcontroller (MCU) coordinatesactivities both autonomously and while under control of the patientcharger and prescription pad; and a battery switch. The Battery Switchtypically protects the battery from over-discharge, and may limit thebattery usage, as illustrated in FIG. 12C.

For example, when the battery voltage goes below 3.2V for ≥100 mS thebattery may be disconnected by the battery switch unless the MCU hasoverridden the disconnection. Similarly, when the battery voltagewonders above 3.4V the battery may be connected and stays connecteduntil the battery drops below 3.2V. During initial power up theBatDiscon(nect) SPI register may keep the battery and reference voltagedisconnected until the MCU enables the battery, which may permit a shelflife in excess of one year. The MCU can at any time override all of thislogic with the SPI register BatRecov(er) that may charge the battery aslong as VCHARGE is present. Once the battery has recovered the MCU canrelease BatDiscon and the system may return to normal operation.

In some variations, the Voltage Supply Switch (VSW) typically turns onthe main supply powering up the MCU and peripherals, as illustrated inFIG. 12D. For example, when the patient charger is connected andproviding a sufficient electromagnetic force to power up the charger theCHARGER_ON signal is asserted, VCHARGE is energized. Even if the batteryis disconnected, and the VSUP(ply) switch is closed; as long as the MCUis powered and holds the VSUP_ON signal the VSW switch is closed. A RTCINT(terupt) pulse is latched enabling the VSUP. The MCU typicallyreceives the latched version of the RTCALARM since: (1) the RTCINT pulsemay have turned off by the time the MCU is powered, and (2) an alarmcould be missed if the RTC Alarm bit comes in just before the SPIALMACK(nowlege) bit is reset locking up the system until the nextcharging session, and (3) the patient charger is removed and the MCU isbeing shut down and the RTCALARM occurs such that the interrupt ismissed.

Any of the microstimulators described herein may transition throughseveral operating modes as shown in the state diagram in FIG. 13. Modesdiscussed here are primarily controlled by software, hardware orfirmware. Based on this exemplary state diagram, the following statesmay be enabled: StartState, BatteryDisconnected, BatteryTest,BattteryRecovery, Timekeeping, Charging, Programming and Dosing. In theStartState, the battery may be inserted (e.g., in manufacturing) at50-75% percent charged. On insertion and power up the system shouldautomatically disable the battery. The BatteryDisconnected state applieswhen the battery is disconnected whenever the voltage drops below 3.2V.Once the battery is disconnected it may be tested, the BatteryTest statecan be entered when the Patient Charger placed within range of themicrostimulator. The BatteryTest state may apply once the PatientCharger is powering the microstimulator the battery can be tested.However, to enter the BatteryRecovery state, the Prescription Pad may beconnected to the patient charger. In the BatteryRecovery state, the MCUmay be commanded by a clinician to recover the battery. Once therecovery process is started the microstimulator enters the Chargingstate. If the Patient Programmer is removed before the battery chargesto 3.4V the hardware may disconnect the battery.

The TimeKeeping state applies while the battery is connected. The systemis therefore always tracking time. After the battery is installed thetime tracking may start counting at zero. By convention, this startdate/time may be based on Jan. 1, 2000, 12:00 Midnight (though anyappropriate date/time may be used). The correct time may not beavailable until the Charging state is entered. The Charging stateapplies when the Patient Charger is sufficiently close to themicrostimulator, the charging circuit is energized and the Chargingstate is entered. Upon entry to this state the real-time-clock in themicrostimulator is synchronized to the crystal controlled time base inthe patient charger. Two sub-states are possible while in the Chargingstate: Programming and Dosing states. The Programming state occurs whenthe external controller (e.g., a prescription pad) is connected thePatient Charger the Clinician can program, maintain, and diagnose themicrostimulator. In the Programming state Dosing may be disabled,however the patient can be stimulated with Test Stimulus through thePrescription Pad. Once the Prescription Pad is disconnected Dosing mayresume.

The Dosing state is typically entered through an RTC Alarm. RTC Alarmscan occur while in the Charging state or while the microstimulator is inthe TimeKeeping state. The Dosing state may start stimulating thepatient for the allocated time and then exit back into Timekeeping modeif the Patient Charger is not present or fall back into the Chargingstate. Note that the Charging state can be entered while in the Dosingstate, there are no differences between the two Dosing states.

The microstimulator may be hermetically sealed by laser welding in a dryhelium argon environment with an integrated bake-out laser weldingsystem. As mentioned above, different sizes of microstimulators may beprovided to accommodate different size patient nerves. For example,three versions of the microstimulator may be made available toaccommodate the different vagus nerve sizes. Overall, the weight of thedevice is set to have a similar density to water. In some variations themicrostimulator may be coated with a non-stick coating such as Teflon toavoid long term adhesion to the POD. Specific mechanical dimensions ofthe microstimulator are illustrated in the diagram of FIGS. 21A-C. Withreference to FIGS. 21A-C, Table 7 (below) illustrates exemplary sizevariations of the one embodiment of a microstimulator as described. Thedimensions and ranges for each dimension are exemplary only.

TABLE 7 Designator Explanation Minimum Maximum Body Length MinimizeIncision   20 mm Body Width Minimize Displacement 6.05 mm 6.15 mm BodyHeight Minimize Displacement BW Bandwidth to reduce conductive shadowseen by the charging field may be minimized to reduce energy loss andheating. The surface of the device in contact with any tissue cannotexceed a temperature of 2° C. higher than the surrounding tissue.Heating of conductive metal in the shadow can be reduced by increasingresistance (e.g. Ti 6-4) and thinning material. LTR Length TransitionRadius-maximized to smooth transition against vasculature and musclesVagus Minimized to reduce   18 mm Nerve the length of requiredDissection dissection Electrode Gap required to stimulate  7.5 mm    8mm Gap the nerve efficiently across mylenated fibers WTR Widthtransition radius should be maximized to smooth transition againstvasculature and muscles VGW Vagus Nerve Width 2, 3, 4 mm shouldaccommodate three sizes VGH Assumed to be about 75% of VGW CHD Channeldepth should be maximized to contact as much of the nerve as possibleand assure that it does not slip off nerve.

In the exemplary embodiment shown in FIG. 21A, for example, theconcentric circles on the left, highlighting the outer circle, indicatethat this variation corresponds to the largest size of implant, and thenumerical/alphanumerical marking on the far right may provide a uniqueidentifier for the implant.

In some variations, a large silicon die may be moved to the ends of themicrostimulator as far away from the center of the coil as possible. Theelectronic Assembly may use a hybrid that may support approximately 4signal layers. The ASIC may be wire bonded bare die.

The power source may be a battery or other power storage device,typically having a capacity of 200 μA, and an average drain of 100 μA orless when the circuit is active. Standby drain may be less than 50 nA.The charge time at 37° C. may be less than 20 minutes to achieve 75% ofcapacity at a 1 mA (5C) charge current. The maximum current into batteryduring short circuit failure is typically <5 mA. In some variations, thesize of the battery is ≤0.65 mm thick×≤7.5 mm long×≤4.8 mm wide. Inanother variation, the battery is <0.4 mm×18 mm×4 mm; in a thirdembodiment, the battery is <0.4 mm×25.4 mm×4 mm. In general, the batterymay have two silver palladium terminals or equivalent that may allowsoldering, resistance welding, or silver epoxy to ceramic substrate andbe <1.5 mm wide by >2 mm long. Furthermore, the battery may be capableof >1 mA peak discharge current, and may be sealed with an aluminum foil16 microns thick that may allow storage in air for up to 1 year. In somevariations the preferred chemistry of the battery is Lithium PhosphorusOxynitride (LiPON) with a LiCoO2 cathode and Lithium anode. For example,the battery may have an internal resistance that may be <300Ω (NormalMinimum Operating Voltage (3.6−1 mA*300′Ω=3.3 V minimum operatingvoltage). The Low voltage cutoff may be ≤3.0V, the self discharge <20%per year; capacity Loss may be <20% over 300 cycles.

As described above, any of the microstimulators may typically includeone or more antenna for communicating with a controller and/or charger.The dimensions of the antenna may be, in various examples,approximately: <1.5 mm thick×<12 mm long×<4.8 mm wide; <2 mm×<10 mm×<4.5mm; <2 mm dia×18 mm long; and <2 mm dia×25 mm long. The construction maybe ferrite with a design to minimize the MRI imaging artifact. Theantenna may be able to produce 5 mW at a voltage of at least 2 volts.

The electrode of the microstimulator may provide a nerve contact areaequal to approximately ½ the surface area of the nerve for at least alength of 5 mm Minimum electrode area=2 mm (min vagus diameter)×π×5 mm(min length)×½ circumference=15 mm2 For example, a vagus nerve diameterof 2-4 mm may be supported. In combination with the POD, less than 1 mmof total gap may be allowed around the vagus, indicating three sizes oradjustable electrodes. The bipolar Impedances of the electrodes may beless than 1000 ohms (real component).

In some variations (such as the variation illustrated above in FIG. 3E),the microstimulator may be implemented on a multi-chip hybrid substrateand consist of the following components: Microcontroller, ApplicationSpecific Integrated Circuit (ASIC), LiPON Rechargeable Battery, andvarious discrete components. The functional partitioning andspecifications is shown in FIG. 22. In this example, the MCU (e.g., aSTM8L151 Micro Controller Unit or MCU) in a chip scale package may beused. The CPU may clock at least as fast as 1 MHz during required CPUintensive operations and during Patient Charger operations. The clockmay be calibrated to with ±1% over life. The MCU may have a low powerlow frequency clock to drive timer/counters of at least 10 KHz to timeperiods between biphasic stimulation pulses. Non volatile memory maycontain at least 16 KB program and data may withstand 10,000 writecycles with a retention time of 20 years. At least 1 KB of very highusage EEPROM may be available for writing parameters such as exceptionlogs. A UART Asynchronous Receiver/Transmitter is set to receive andtransmit a maximum of 4800 baud and the frame may be configured asfollows: 1 start bit, 8 data bits, and one stop bit. The UART may havethe ability to detect overruns, noise, frame, and parity errors. The 8data bits may be encoded using 6b/8b encoding to maintain ASICapproximate DC balance. The Analog Digital Converter (ADC) may have theability to detect a 0.5% change in field strength (0-50V), BatteryVoltage (0-4.5V), Voltage across Electrode contacts 0-20 V and a 0.1%change in temperature from the interface MCU sensor. In this example,two timer/counters may be used to generate timing pulses for bipolarcurrent source with an accuracy of (±5%) and 25 uS increments between0-1000 uS.

The ASIC may include an RTC that is implemented with an ultralow poweroscillator, counter, and comparator. A semiconductor junction mayprovide a voltage reference to drive a low frequency oscillatorstabilized by body temperature. This oscillator may clock a 40 bitregister that may track absolute time for a period of at least 200years. A comparator may generate an RTC Alarm pulse when a match occurs.The counter is intended to be corrected with a read and write each timethe system is charged. The RTC and the BSW together may operate with <50nA. The clock frequency may be 128±64 Hz with a drift less than ±0.25%over an entire day in a 37° C. controlled environment. The frequency maybe able to be calibrated to ±0.1% within 30 seconds (100/(64 Hz*30seconds)≈0.05%. The oscillator may run at a higher rate than once perminute and be divided down. The MCU may have the calibration constantprogrammed in at manufacturing time and may write the adjusted number of‘ticks’ to the ASIC RTC. The 48 bit counter may be read/write throughthe SPI port and double buffered to reduce software complexity. A 48 bitcomparator register may generate a RTC-Alarm pulse that is routed to theVoltage Supply Switch. The comparator may be double buffered and beread/write through the SPI port.

The Charger shown in FIG. 22 includes a charger circuit that may consistof a voltage booster followed by a linear regulator that may accept arange of 2-7 volts and convert it to 4.05-4.18 volts with a maximumcurrent limit of 5 mA. In addition, the device may include a BSW. TheBattery switch functionality was described above (in reference to FIG.12C). The battery switch may include a power of the BSW and RTC that is<50 nA. When the battery is disconnected the power may be <15 nA. Thebattery may be disconnected from the VCHARGE line when the batteryvoltage drops below 3.3V±10% for some time value (e.g., on the mSscale). The battery may be reconnected when the battery voltage risesabove 3.4V±10% for some time (on the mS scale). Demod/Mod Communicationsare enabled through a combination of a RS-232 port on the MCU and amodulator and demodulator pair in the ASIC. In order for properDemod/Mod operation the following rules may be applied: bits may bealternated so that no more than two bits of the same polarity may be insequence. This maintains the required balance for slicing the data; datamay be grouped in packets and a two word preamble may be required;packets may be checked with a CRC code before the data is utilized (alsoalternating bit violations would required packet rejection); a datastream may be recovered by an amplitude shift keying demodulator mayhave a rectifier followed by a single pole low pass filter at 2 x the4800 bps baud rate and limit the voltage to Vsupply; the data slicer maycompare the data stream to a long term envelope of the data (theenvelope may consist of a low pass filter with a cut-off at about symbollength (10 bits) or 480 Hz); the data modulator may load the resonantcoil with a predetermined resistance; and the data modulator may utilizea snubber to minimize the resulting spectral splatter.

As illustrated in FIG. 22, the Vsupply Regulator may help keep the MCUvoltage regulated and ≥2.0V and <3.3V and can be turned on by RTC, andheld on by RTC and/or MCU. The Charge Pump provides a 2× voltagemultiplier that doubles battery voltage that supports an equivalent loadof 100K′Ω and a peak load of 5 mA and a peak average load of 0.5 mAusing 10,000 pF capacitors. The DAC is an 8 bit current mode DAC thatdrives one of two current mirrors (sink configuration) to produces a0-5,100 uA±5% in 20 uA steps. The DAC may have a full scale settlingtime of <luS to a resolution of 6 bits. Calibration may be supported inmanufacturing at the system level using data that is either store in MCUor ASIC. The Bipolar Current Source in the variation is an H-bridge pushpull configuration that may be used to drive bipolar electrode. Twoanodic switches and two cathodic current sources are a possibleconfiguration. Capacitive coupling using high quality discrete ceramiccapacitors is required to double voltage swing and prevent DC flow outhermetic capsule. Discharge resistors of 100 KΩ±30% are required todrain resulting voltage offset that builds up between output capacitorsand H-bridge. In this example, an analog multiplexer having voltagemeasurement facility measures: battery voltage (1 s sample rate); Demodsignal strength (1 mS sample rate), and a differential amplifier formeasuring voltage across electrode (25 uS sample rate). Factorycalibration of each of the three values may be supported with both slopeand offset and stored in the MCU EEPROM. The implant may also include aversion number, such that the silicon version number is accessiblethrough SPI port. The format may be one byte sequential indicatingdesign mask submission. The example in FIG. 22 also shows a Zener thatprovides overvoltage protection from electromagnetic fields using aZener voltage clamp <6 V (a higher level may result in less powerdissipation in Microstimulator) with a minimum power dissipationcapacity of watt (which may set upper limit based upon semiconductorprocess and Charger circuit optimization). DC Protection may be providedby output capacitors to prevent DC leakage in excess of 50 nAindependent of any software or circuit failures. Capacitors may be atleast 47 nF. The MCU-Watchdog timer runs when MCU runs to restartprocessor in case of software hang-ups.

Example 1: Microstimulator

In this example, the microstimulator is a rechargeable neural stimulatorthat attaches to the vagus nerve and delivers current through bipolarplatinum contacts against the nerve, as illustrated in FIG. 1B (103).The microstimulator battery may be charged by an external charger(“energizer”) and the energizer also functions as the communicationgateway for the external controller (“prescription pad”). TheMicrostimulator in this example is physically housed in a rigid hermeticcapsule with an attached electrode saddle. The hermetic capsule in thisexample is composed of an Alumina toughened Zirconia tube with metalends brazed onto the ceramic tube. Brazing joints may use a nickeldiffusion process or gold braze. The metal ends are an alloy of Titaniumto reduce electrical conductivity and increase braze-ability. As shownin FIG. 23A, within the hermetic capsule is a resonator, hybrid withattached electronic parts, and batteries. The hybrid assembly issuspended by metal clips that also make contact to the metal ends. Theelectrodes are molded into a polymer saddle and electrical contact ismade to the metal ends with a laser weld.

The active electronics in this variation of a microcontroller consist ofa custom ASIC (CCAD08) along with a MCU (STM8L152) show in the blockdiagram in FIG. 24A. FIG. 24B shows a block diagram of the ASIC. Thepassive electronics of the microcontroller consist of a resonator, zenerover voltage protection diodes, voltage doubling diodes, and filteringcapacitors. The electrodes have in-line blocking capacitors to preventDC flow. A thermistor shuts the device down in over temperatureconditions. And finally a battery provides power to the system.Referring to the block diagram in FIG. 24A, the system operates asfollows. Power is received by the resonator. A rectified AC coupledversion of the TANK voltage (RFIN) is sent to the telemetry circuitwhere telemetry data amplitude modulated on the carrier is detected anddemodulated. RFIN also feeds through another rectifier that doubles thevoltage at PWRIN.

The Power Management circuitry has many functions. The first function isto regulate the voltage to charge the battery as this voltage needs tobe controlled within a few tens of millivolts to maximize the capacityof the battery without damage. Supply switches supply the ASIC and MCUexternal power even if the battery is damaged or not present allowingfunctions such as battery recovery, initial battery charging anddiagnostics. A VDD regulator reduces the battery voltage to 2.5V so thatMCU will not be damaged and provides a reference for the MCU analog todigital convertor so that impedances can be measured accurately. Supplyswitches also route battery power to the MCU when the Microstimulator isrunning autonomously (no Energizer Present) which is the normal mode ofoperation. Voltage comparators that are calibrated in manufacturingprotect the battery from over discharge by first shutting off allfunctions other than time keeping and finally putting the device inshelf mode until the battery is charged. Voltage comparators short thetank out when either an over-temperature or over-voltage condition ispresent protecting the device. A load stabilization circuit produces aconstant load of 0, 1, 2, or 3 mA stabilizing the load to improve therobustness of communication. Turing on the ADC in the MCU can forinstance increase the load from 200 uA to 1 mA. Two voltage referencesare generated, one that operates when charging, the other that operateswhen the battery levels are periodically checked. A power on resetassures that when the system is powered during manufacturing or when theMCU is powered after an Alarm event that the logic operates withouterrors.

The Telemetry sub-system extracts a clock from the carrier forManchester decoding, extracts the envelope or the carrier for datadetection. Then it slices the analog signal to derive binary data. Thisbinary data with the extracted carrier clock is used to convert theManchester encoded data to NRZ format that can be interpreted by theUART in the MCU. The UART set to the same baud rate is able to translatethe asynchronous stream to 8 bit systems. The Manchester encoder must beprogrammed for either a 1200 or 4800 baud rate by the MCU.

Back Telemetry data, that is data from the Microstimulator to theEnergizer, is kept in NRZ format. This data is always sent as a responseto an Energizer packet. The UART data causes a load shift keying (LSK)modulator to short RFIN to ground effectively unloading theMicrostimulator from the Energizer coil. In order for the Energizer toreceive this data is must continue to send an unmodulated carrier to theMicrostimulator.

The Oscillator block in the ASIC is an extremely low power RC circuit(<50 nA). It is body temperature stabilized and driven by a regulatedvoltage supply. The clock is further calibrated during the manufacturingprocess. The oscillator drives a 40 bit counter at 100 Hz configured asa timer. The Timer has a programmable ALARM that powers-up the MCU withthe wakeup time configured by the MCU. Power is preserved by onlyrunning this timer and then powering up the system/MCU for scheduledactivities. A typical activity is dosing the patient with stimulationusing the Stimulator block, usually about once per day. This oscillatoris only accurate to about +/−3 minutes a day so it when the Energizer isattached the Timer time is adjusted to the very accurate Energizer time.

Another function the timer has is to command the circuitry to check thebattery level about once per hour as continuous checking would requiretoo much power.

The Stimulator block has contains an 8 bit current DAC configured as anH-bridge enabling generation of balanced biphasic pulses and thestimulation voltage and inverted stimulation voltage. The stimulationvoltage is generated from a 2× voltage multiplier defining thestimulation compliance rail. Also included in this block is adifferential amplifier that measures the voltage across the complexphysiological load. And at a constant current the voltage waveformmeasures is proportional to the complex impedance. If the voltage hitsthe compliance rail the stimulation is no longer delivering a constantcurrent, a condition to be avoided.

The MCU controls the ASIC through the SPI accessible Registers. Throughthese registers the MCU drives the stimulator digital-to-analog convertto stimulate the patient for a particular duration. The MCU also hasaccess to many voltages on the ASIC through the Analog Multiplexer(AMUX).

Very accurate settings are required to not only mark time but alsomanage the battery. The strategy for managing the significant variationsin silicon is to utilize numerous calibration Digital-to-Analogconvertors implemented in the ASIC to adjust all the voltage andfrequency references. This process is done using calibrated testequipment in manufacturing and then stores these values ors in MCUEEPROM. These values are stored in the SPI registers in the ASIC,typically power is never removed, but it is these values can berefreshed by the MCU.

The operation of the ASIC in this example may be understood through anunderstanding of each functional block, explaining the system-levelimplications. The system schematic is shown in FIG. 15, and a high levelASIC schematic is shown in FIG. 16.

Any of the microstimulators described herein, including this exemplarymicrostimulator, may include thermal protection. Although the Energizerthrottles the magnetic field so that the Microstimulator does notoverheat or saturate the telemetry communications, it is possible thatif these controls fail, the Microstimulator temperature could climb over41° C. potentially causing damage to tissues. The primary source of heatwill be the coil. Normal body temperature itself can reach 38° C.leaving a narrow range of thermal operation as shown in the diagram inFIG. 25A. The black diagonal line is temperature rise of the coil withpower absorbed in air and may have a lower slope in the body. Themaximum level of energy transfer is about 13 mW, when the battery isfully discharged it requires about 3 mW of power to charge, this chartindicates that the system can operate safely while absorbing between5-10 mW of power.

As a second line of defense to prevent overheating, a thermistor ismounted at the base of the coil so that when the temperature reaches apoint so that the temperature on the electrode contacts could reach 41°C., the coil will be shorted, dramatically reducing energy absorption.Given that thermistors are only accurate to about 2° C. and the thermalshutoff circuit in the ASIC has even a wider variation, an externalthermal threshold resistor is selected during the manufacturing test sothat the shutoff can be controlled to within half of a degree C.

The battery being utilized in this example is a solid-state LiPON with anominal voltage. The Recharge time is 20 minutes to a capacity of 80%.The charging voltage range is 4.00-4.15V where the optimum value isestimated to be 4.08V. The battery supports more than 5000 cycles with a10% depth of discharge. The discharge curve for the battery is shown inFIG. 26.

The input impedance of this battery is fairly high and must be managed,since the system may require 8 mA current spikes for a duration of 1 mSat a rate up to 20 times per second. These high current pulses areenabled with a large 22 uF capacitor paralleled with 3 50 uAhr cells.

This variation of a microstimulator also includes a resonator that istypically a coil and capacitor designed to resonate at 131 KHz±2%. Thecoil is constructed with many turns of magnet wire with a targetinductance of about 20 uH. An external high quality NPO capacitor isused to set the tank frequency. NPO is chosen due to a low dielectricloses (ESR) and high accuracy. It is possible that a second smallertrimming capacitor may be required. This capacitor must be able totolerate the high voltages that can be induced on the coil. As a safetyprecaution zener diodes limit the voltage across the capacitor providinga second level of protection to the Energizer limiting the generatedmagnetic field.

The coil uses a ferrite coil to concentrate the flux. A long thin designwas selected to improve the efficiency and limit the amount of requiredferrite for increased MRI compatibility. The long ferrite increases theeffective permeability P α (uA)2. The design of the ferrite is shown inFIGS. 27A-D. Care must be taken to minimize the amount of RFabsorbing/conductive material shielding the resonator. FIG. 28 is agraph of the Resonator in free air vs. a coil with the hybrid andhermetic end caps sealing the hermetic capsule. In this graph, astronger magnetic field is required to overcome the shielding. The useof ceramic and highly resistive alloys such as Grade #36 Titanium isused to reduce shielding.

During system startup the resonator typically cannot start the systemwithout resulting in chatter and unpredictable states. This problem issolved by limiting the amount of power that can charge the battery andcapacitors with current limiters. The operation is shown the compositegraph of FIG. 29 with limiters in place.

Returning now to FIG. 24B, The CCAD08 ASIC works with a Micro ControllerUnit (MCU) to perform all of the required functions for theMicrostimulator product defined in herein. The functions of the ASICinclude electrode stimulation, wireless communication interface,wireless supply recharge, interval timing, and power supply management.Further detail of the ASIC properties is provided below for thisexemplary embodiment.

In this example (shown in FIGS. 24A and 24B), the Battery Charger isconnected to the PWRIN signal. It produces a regulated output voltage[VCHARGE] of ˜4.2V from an input voltage at PWRIN ranging from ˜4.3V to˜20V. The VCHARGE output is regulated by a linear amplifier thatcompares an internal voltage reference [vref3] to a feedback signal fromVCHARGE. The VCHARGE output is connected through the Supply Switches toa rechargeable battery. The Battery Charger must operate independentlyof other ASIC functions, so it includes its own voltage reference[vref3] and regulated supply [reg3v] that are supplied by PWRIN. Thevoltage reference [vref3] and regulated supply [reg3v] are also used bythe Over-Voltage and Over-Temp Detectors. The output voltage [VCHARGE]can be calibrated by programming an appropriate calibration code intothe VCHARGECAL Register. The Battery Charger also includes logic outputs[in_reg], [ref_good], [chrg_good] that indicate when the circuit is inregulation, when the voltage reference is valid, and when the VCHARGEoutput voltage is ready for connection to the battery.

The Load Controller is connected to the VCHARGE signal. It controls theload current out of the Battery Charger to produce a constant load onPWRIN, and thus constant equivalent impedance at the antenna. Theconstant antenna impedance provides better consistency of the wirelesscommunication. The Load Controller compares the actual load current onVCHARGE to a pre-determined target current, and adds extra load currentto make up the difference. If the actual load current exceeds the targetcurrent, the Load Controller has no function. The target current can beselected to be 3 mA, 2 mA, 1 mA, or 0 mA (disabled) by programming theLOAD_SELECT bits of the DEMODCTRL Register. The Load Controller isenabled by automatically upon the rise of PWRIN.

The Over-Voltage Detect circuit monitors the PWRIN signal and produces alogic output [ov_detect] when the PWRIN voltage exceeds 30V. The output[ov_detect] connects to the Modulator which loads down the RFIN signalto reduce the Q of the antenna network and thus reduces the input power.The circuit includes a comparator that compares a resistor-dividedversion of PWRIN to a reference voltage. The supply and reference forthe Over-Voltage Detect circuit are connected to the reg3v and vref3outputs of the Battery Charger. The voltage threshold has hysteresis, soafter an ov_detect event, the PWRIN voltage must drop below 24V for theov_detect signal to go low.

The Over-Temp Detect circuit monitors the Microstimulator's temperatureby measuring the resistance of an external Thermistor(temperature-controlled resistor). The circuit includes a current sourcethat forces a reference current into the Thermistor through the THERMoutput, and a comparator that compares the THERM voltage to a referencevoltage. The circuit produces a logic output [ot_detect] when the THERMvoltage exceeds the vref3 voltage. The circuit is designed to work witha Thermistor that has a resistance of ˜62K□ at 41 C, so in application,a Microstimulator temperature greater than 41 C will cause theover-temperature detection. The output [ot_detect] connects to theModulator which loads down the RFIN signal to reduce the Q of theantenna network and thus reduces the input power. The supply andreference for the Over-Temp Detect circuit are connected to the reg3vand vref3 outputs of the Battery Charger. The voltage threshold hashysteresis, so after an ot_detect event, the temperature must drop below39 C for the ot_detect signal to go low. The Over-Temp Detect circuitalso includes a calibration mode. The calibration mode can be entered bysetting the CAL_MODE bit of the STIMCTRL register. When in calibrationmode, the response time of the circuit is slowed-down slightly to guardagainst tester-noise induced detection.

The Supply Switches are internal MOS switches that direct the flow ofcurrent between the Battery Charger output [VCHARGE], the batteryterminal [VBAT], and the main supply [VSUPPLY] for the ASIC. The SupplySwitches can be configured to allow the VCHARGE voltage to charge up thebattery through VBAT, allow the VBAT voltage to supply the systemthrough VSUPPLY, allow VCHARGE to simultaneously charge the batterythrough VBAT and supply the circuit through VSUPPLY, or disconnectVCHARGE and VSUPPLY such that only the minimal circuitry on the VBATsupply can operate. The configurations of the Supply Switches arecontrolled by three logic input signals, [charge_sup_on],[charge_bat_on], [vbat_on] that are derived in the Power Control circuitin the Digital block. The Supply Switches block also produces a logicoutput [vchrg_higher] that indicates when VCHARGE is higher than VBAT,and a supply output [v max] which always connects to either VCHARGE orVBAT—whichever is the higher voltage. The vchrg_higher signal connectsto the Power Control circuit and helps determine the Supply Switchinputs. The v max supply connects to the supplies of various levelshifters that would otherwise malfunction under certain supplyconditions.

The Reference circuit is connected to VSUPPLY, and produces an outputvoltage [vref1] and several output currents [iref_n] for use by thevarious analog circuits in the ASIC. The reference voltage is created bya typical bandgap reference circuit. The output voltage [vref1] isbuffered to provide a low-impedance 0.6V reference. The vref1 output canbe calibrated by programming an appropriate calibration code into theVREF1CAL Register. The circuit includes a current reference, whichutilizes the reference voltage [vref1], an amplifier, and an externalresistor connected to the RREF pin to create a precise reference current[iref]. The circuit also includes current mirrors to produce severalindependent but matched current outputs [iref_n].

The VDD Regulator is connected to VSUPPLY, and produces a regulatedoutput voltage [VDD] of 2.5V from an input voltage at VSUPPLY rangingfrom 3.3V to 4.2V. The VDD output is regulated by a linear amplifierthat compares the internal voltage reference [vref1] to aresistor-divided feedback signal from VDD. The VDD output serves as thesupply for various ASIC circuits. The VDD output is also connectedthrough a MOS switch to the VDD_PAD, which is intended to supply anexternal MCU, with a 220 nF bypass capacitor. The VDD_PAD switch iscontrolled by a logic signal [vdd_to_mcu_n], which is derived in thePower Control circuit. In normal operation, the total load current onVDD and VDD_PAD ranges from 100 uA to 2 mA.

The Charge Pump is connected to VSUPPLY, and produces an un-regulatedoutput voltage [VSTIM_OUT] of approximately 2 times VSUPPLY for VSUPPLYranging from 3.3V to 4.2V. The Circuit uses a combination of internalswitches and external capacitors. One capacitor is connected between theCAP1N and CAP1P pins, and another is connected between VSTIM_OUT andCPGND. The Charge Pump is enabled when the VS TIM_EN bit of the STIMCTRLRegister is set. The VSTIM_OUT voltage is produced by first charging theCAP1 capacitor from VSUPPLY to CPGND, and then switching the low side ofthe capacitor to VSUPPLY and the high side of the capacitor toVSTIM_OUT. The charging and switching phases are alternated at thefrequency of an internal charge pump oscillator. Each period of theswitching transfers a small packet of charge onto the VSTIM_OUTcapacitor until VSTIM_OUT reaches ˜2×VSUPPLY. The VSTIM_OUT output isintended to be connected to the VSTIM_IN pin, to provide the supply forthe output stage of the H-Bridge. The voltage doubling is required toprovide enough supply headroom and low enough output impedance tosupport up to 5 mA peak and 100 uA average stimulus current output. WhenVSTIM_EN is not set, VSTIM is connected to VSUPPLY through a relativelyhigh (>100K) resistance.

The Battery Monitor circuit measures the battery voltage [VBAT] andproduces two logic outputs [bat_good], [bat_not_dead] according to twoprogrammable voltage thresholds. The thresholds are programmed by theBATMONTRIM Register, with bits 7 through 4 selecting the bat_goodthreshold and bits 3 through 0 selecting the bat_not_dead threshold. Thebat_good threshold can be programmed in the range of 3.5V to 4.0V, witha 33 mV resolution. The bat_not_dead threshold can be programmed in therange of 3.0V to 3.5V, with a 33 mV resolution. The Battery Monitorincludes two nearly-identical circuits, each consisting of a comparatorthat compares a resistor-divided version of VBAT to the internalreference voltage [vref1]. The supply for the Battery Monitor isconnected directly to VBAT. To minimize power consumption, the circuitis normally disabled, and only enabled periodically for short durationsto make the measurements and latch the results. The circuit alsorequires the vref3 voltage from the Reference block to make accuratemeasurements, so the Reference block must also be enabled each time theBattery Monitor is enabled. The measurement sequence is controlled bytwo logic inputs [bat_mon_en], [bat_mon_latch], which are derived in thePower Control circuit in the Digital block. The bat_not_dead circuitincludes an additional feature that creates a single logic pulse[rst_osc_en], which resets the OSC_EN bit in the PWRCNTRL Register anytime a battery measurement results in bat_not_dead being false (batteryvoltage less than threshold). This feature forces the Microstimulatorinto Storage Mode when the battery gets too low, but allows for recoverythrough an external charger.

The POR circuit monitors the VBAT and VDD voltages, and provides logicsignals [nreset_vbat], [nreset_vdd] that hold logic circuits on theirrespective supplies in the reset state when the supply voltage is toolow for valid logic operation. The nreset_vbat signal is connected tovarious digital circuits on the VBAT supply, and nreset-_vdd connects tovarious digital circuits on the VDD supply. The POR block includes twonearly-identical circuits, each consisting of a crude voltage reference,a supply voltage divider, and a comparator. Both circuits must beenabled at all times, so the power consumption in each must be kept to aminimum, and the circuits must work independently of other ASIC circuitblocks. The nreset_vbat signal is set high when VBAT rises to greaterthan 1.8V, and resets to low when VBAT falls below 1.6V. The nreset_vddsignal is set high when VDD rises to greater than 2.0V, and resets tolow when VDD falls below 1.8V. The ASIC also includes a similar functionto produce nreset_vreg, but that signal is generated in the Oscillatorcircuit.

The IDAC converts an 8-bit digital word into an output current [istim]that is linearly proportional to the value of the digital word. Thedigital word is programmed by writing to the IDAC Register. The outputcurrent [idac] sinks into the IDAC from the H-Bridge, and ranges from 0uA to 127.5 uA, with a 0.5 uA step size. The IDAC is supplied by VDD,and is enabled by the IDAC_EN bit of the STIMCTRL Register. Thereference current for the IDAC [iref_dac] comes from the Referenceblock.

The H-Bridge sources the current [istim] into the IDAC, multiples thecurrent by 40, and mirrors the 40× current to provide sourcing orsinking output currents to the Electrode pins [E0, E1]. The H-Bridge isenabled by setting the HBRIDGE_EN bit of the STIMCTRL Register. TheH-bridge also includes switches that are controlled by the MCU's timingsignals [PHA, PHB] such that the output current to the Electrodesreverses its polarity at each timing phase change. The output current,which flows through external series (2.2 uF) capacitors to the load,ranges from 0 mA to 5.10 mA as determined by 40× the IDAC setting.

The DiffAmp monitors the voltages at the Electrode pins [E0, E1], andproduces an output voltage [vdiff] that is proportional to the voltagedifference between E0 and E1. The circuit is supplied by VDD and usesthe main internal voltage reference [vref1] as the zero-point of theoutput range. If the E1 voltage is greater than the E0 voltage, theoutput [vdiff] ranges between vref1 and VDD. If the E0 voltage isgreater than the E1 voltage, the output [vdiff] ranges between vref1 andVSS. If the E1 voltage is equal to the E0 voltage, the output [vdiff]equals vref1. The DiffAmp is enabled by setting the DIFFAMP_EN bit ofthe STIMCTRL Register. The output voltage [vdiff] is connected to theAnalog Multiplexer (AMUX) which connects the vdiff signal to an Analogto Digital Converter (ADC) on the MCU.

In this example, the Demodulator is connected to the RFIN pin which isconnected to the antenna network. The antenna receives wireless energytransmitted from the Charger/Programmer at 127-135 KHz. Telemetry datais Manchester Encoded, Amplitude-Shift-Keyed (ASK) at either 1200 or4800 baud. The Demodulator includes an attenuator and a series ofhigh-pass and low-pass filters and a comparator to extract theManchester Encoded data from the modulated input signal. It alsoincludes a comparator to extract the clock signal from the carrierfrequency. The attenuator reduces the RFIN signal amplitude to VDDlevel, and sends the attenuated signal to both the clock comparator andthe data comparator. The extracted data and the clock are connected to aprogrammable counter to decode the Manchester Encoded data and produceNRZ data at the RX pin. At power-up, the counter is hardware-preset to acount of 20 to provide a sampling period equal to ¾ of the 4800 bauddata period. The counter can be programmed to any value from 0 to 255 tosupport a wide range of baud rates, including 1200 baud, by writing theDEMODCNT Register. To set the count to the register value instead of thehardware default, the DEMOD_CNT_SEL bit of the DEMODCTRL Register mustalso be set. When DEMOD_CNT_SEL is not set, the counter uses thehardware preset count of 20. The attenuation of RFIN to the Demodulatorinput can also be programmed to values of 0.60, 0.50, or 0.33 toaccommodate a range of input signal amplitudes by writing the DEMOD_ATTbits of the DEMODCTRL Register. Finally, the carrier-extracted clock canbe replaced by an external clock signal driven to the DTEST pin bywriting the RFCLK bit of the DEMODCTRL Register. The Demodulator issupplied by VDD and is enabled by the charge_sup_on signal from thePower Control circuit, which indicates when the Battery Charger issupplying power to the rest of the ASIC through the Supply Switches.

The Modulator is connected to the RFIN pin. The circuit consists of alarge NMOS switch from RFIN to RFGND that is controlled by a logicsignal at its gate. Back-Telemetry data transmission is controlled bythe MCU by driving NRZ data into the ASIC's TX pin. Under normalconditions, the TX signal passes directly to the gate of the Modulatorswitch, such that when TX is low, the RFIN is unaffected, and when TX ishigh, the Modulator switch turns on and increases the load on RFIN. Theload switching produces a Load-Shift-Keyed (LSK) signal at the TelemetryAntenna when the antenna is receiving un-modulated energy at the 127-135KHz carrier frequency. The Charger/Programmer circuitry detects theresulting voltage and current changes in the carrier driver, and decodesthe LSK data to reproduce NRZ data. Under hazard conditions, theOver-Voltage and/or Over-Temp Detect circuits control the gate of theModulator switch, turning the switch on, regardless of the NRZ data onTX pin.

The Oscillator creates a 100 Hz square wave clock [clk100] for use bythe Alarm Timer. The Oscillator must remain powered by VBAT while theremainder of the system is asleep, so the Alarm Timer can trigger asystem wakeup. To maximize product-life between charging sessions, theaverage supply current of the Oscillator must be extremely low (<50 nA).The Oscillator is enabled by the OSC_EN bit of the PWRCTRL2 Register,which activates Timekeeping mode. When OSC_EN=0, the Oscillator isdisabled, and the ASIC is in Shelf-Mode, its lowest-current state (<5nA). Under normal conditions, the Oscillator will be enabled upon thefirst use of the Microstimulator, and remain on indefinitely. TheOscillator frequency can be calibrated by the lower 6 bits of the OSCCALRegister, with a frequency step-size of 5 Hz. For more precise timing,the MCU can measure the precise Oscillator frequency with a highfrequency timer, and then adjust timing parameters according to themeasured frequency. The Oscillator is required to maintain timingaccuracy of 3 minutes/day between charging sessions, so the Oscillatorfrequency must be independent of the VBAT voltage, and stable over theexpected operating temperature range.

The Voltage Regulator (VREG) creates a pseudo-regulated supply voltage(VREG) for the Oscillator, Alarm Timer, and Control Registers. Theprimary goal of the VREG circuit is to provide the Oscillator with themeans to reject VBAT supply variations in the creation of the 100 Hzclock. To maximize product-life between charging sessions, the averagesupply current of the VREG must be extremely low (<30 nA). To meet theultra-low power requirements, the VREG circuit uses a Sum-Of-Thresholdsapproach to the voltage regulation. The circuit consists of abias-current generator, a current mirror, and a stack of gate-drainconnected NMOS and PMOS devices. The current mirror forces currentthrough the MOS devices to produce a voltage that is proportional to thesum of the NMOS and PMOS thresholds. Since the MOS thresholds have largeprocess variations, the VREG voltage also has high process variation,but the variations over temperature and VBAT conditions are small, sothe primary goals are met with a very low overhead power. The VREG alsosupplies the Alarm Timer and Control Registers. Both of these circuitsare enabled for most of the Microstimulator life, so they require asupply with very low overhead power. To minimize switching transients onVREG due to the digital functions, an external 1 nF capacitor should beconnected between VREG and VSS. The VREG circuit also includes a PORcircuit for the digital blocks on the VREG supply. The output of thecircuit (nreset_vreg) is connected to the nreset inputs of the AlarmTimer and Control Registers. The nreset_vreg output is high when VREGexceeds 1.5V. When VREG is less than ˜1.5V, nreset_vreg holds theControl Registers in their reset states. In particular, the OSC_EN bitis set to 0, and the ASIC enters Shelf-Mode.

The Analog Multiplexer (AMUX) is supplied by VDD. It selectivelyconnects one of multiple analog signals to the AMUX pin which isconnected to the ADC on the MCU. The AMUX is enabled by setting theAMUX_EN bit of the AMUX Register. The input signal selection iscontrolled by the lower 3 bits of the AMUX Register. The inputs to theAMUX are; the DiffAmp output [vdiff], the wireless power input [PWRIN],and the battery voltage [VBAT]. Each of the signals must be gained orattenuated as appropriate such that the full-scale range of expectedinputs matches the full-scale input range of the ADC on the MCU. TheAMUX is also used to connect various other analog signals to the AMUXpin to support ASIC test and debug. The details of the AMUX signals,their corresponding selection codes, and their gain/attenuation factorsare defined in the Register Definitions section of this document.

The Serial Peripheral Interface (SPI) is an industry-standard SPI Slavemodeled after the SPI Slave in the STM M95010 EEPROM. It provides 1 MHzserial communication access to the ASIC from the MCU, which includes anSPI Master. The Interface include 4 wires, including; serial clock[SPI_CLK], chip select [SPI_CSN], Master-Out-Slave-In [SPI_MOSI], andMaster-In-Slave-Out [SPI_MISO]. The ASIC's SPI supports burst reads andwrites in which the MCU can write a read/write instruction and astarting address, and the read or write multiple successive data wordsfor a range of addresses. The detailed sequences and timing for the SPIread and write procedures are documented in the Timing Specificationssection. The SPI is supplied by VDD to produce logic levels that matchthe MCU's logic levels.

The Control Registers are standard read/write registers that can beaccessed by the SPI. The Control Registers are configured as an array of8-bit registers, each with a unique address. The Control Registersinclude read/write registers that will store device configurations, modeselections, and calibration data. The registers are supplied by VREG andwill therefore retain their contents as long as adequate battery voltageis supplied. The Registers also include two read-only registers; theASICREV Register, which stores the ASIC revision code, and the SUPPLYMONRegister, which includes logic signals representing the status ofvarious power supply monitors. The Control Registers also includeread/write registers used to support ASIC test and debug. The specificfunctions of all the registers and bits are defined in the RegisterDefinitions section of this document.

The Alarm Timer is supplied by VREG. It includes a 40-bit ripple counterregister that is clocked by the Oscillator clock [clk100], and isread/write capable via the Serial peripheral Interface (SPI) as five8-bit registers COUNTER0 through COUNTER4. It also includes a second40-bit read/write capable register and combinational logic that producesa 1.28 s to 2.56 s digital output pulse [rtc_alarm] when the contents ofthe two 40-bit registers match. The rtc_alarm signal is sent to thePower Control block, and to the MCU via the ALARM pin. After the alarmevent has been recognized by the MCU, the rtc_alarm signal can becleared by writing to the RST_ALARM bit of the ALMCTRL Register. Typicaluse of the Alarm Timer will consist of a calibration by the MCUinvolving reads of the ripple counter before and after a fixed timeduration (controlled by the MCU's precise clock, or determined viareference to an external time source accessed via the wireless link).The MCU will calculate a correction factor to translate the ASIC's timebase to the MCU's precise time base, and set the 40-bit Alarm Registeraccordingly. The Alarm time can be set by writing to the ALARM0 throughALARM4 Registers, which are concatenated to form one 40-bit data word.To avoid data integrity problems with the Ripple Counter, the COUNT_DISbit of the ALMCTRL Register should be set prior to writing the RippleCounter, and cleared after the write is complete. The Ripple Countermust also be written in sequence from COUNTER0 to COUNTER4.

The Power Control block includes control logic for the operation of theSupply Switches and the Battery Monitor. The connections between thesesub-blocks and the blocks they interact with are shown in the diagrambelow. The typical supply sequence will begin with the first applicationof the battery. The battery will typically be attached with little or nocharge. After battery attach, an automated tester will charge thebattery directly via the VBAT pin. The Microstimulator will then stay inStorage Mode, with minimal battery leakage until the first applicationof the external Charger. When the external Charger is applied, PWRINbegins to rise, and the Battery Charger begins to turn on. The BatteryCharger monitors the supply conditions, and when PWRIN is sufficientlyhigh, the Power Control circuit turns on Switch1, which connects VCHARGEto VSUPPLY. At this time, the Demodulator and Load Controller also turnon. When VSUPPLY increases, the Reference, VDD Regulator, and VDD Switch(Switch 5) are all enabled, and thus the MCU starts-up. Once enabled,the MCU will set the OSC_EN bit of the PWRCTRL2 register to turn on theOscillator and VREG, and enter Timekeeping Mode. In Timekeeping mode,the Alarm Timer will initiate periodic (every 90 minutes) batterymeasurements. To make the measurements, the Reference, VDD Regulator,and Battery Monitor (Switch 4) are enabled, but the VDD Switch (Switch5), and thus the MCU are off. The Alarm timer will also wake up thewhole Microstimulator whenever the pre-programmed alarm duration hasexpired. When the duration expires, the ALARM pin is set high, and theReference, VDD Regulator, and VDD Switch (Switch 5) and thus the MCU,are enabled. The MCU must then set the MCU_VDD_ON bit of the PWRCTRLregister prior to the Alarm's 1-2 second timeout, to keep itselfenabled. After MCU_VDD_ON is set, the MCU can perform any operation,such as enabling ASIC sub-blocks and running Stim patterns. To return toTimekeeping Mode, the MCU must clear the MCU_VDD_ON bit.

FIG. 30 shows a circuit diagram for a microstimulator including some ofthe elements described above, as well as a switch control block. Theswitch control circuit includes combinational logic that turns on or offthe switches in the Supply Switches block, as well as the VDD_PAD switchand the “check battery” switch within the Battery Monitor. The switchdefinitions and conditions are defined as follows: Switch1 is the switchbetween VCHARGE and VSUPPLY. It is turned on when the system is beingsupplied by the external charger and not by the battery. The gate ofSwitch1 is controlled by the charge_supp_on signal. The logic forcharge_supp_on is as follows: charge_supp_on=charger_on AND NOT[alarm_chk_bat_inprogress]. charger_on indicates a valid output voltageat VCHARGE. charger_on is asserted as VCHARGE rises above the threshold.This threshold must be higher than the point where the internal band-gapreference is valid. The charger_on signal is de-asserted when theinternal band-gap reference is not valid.

alarm_chk_bat_inprogress is the signal from battery monitor statemachine that indicates an alarm initiated battery check measurement isin progress.

Switch2 is the switch between VCHARGE and VBAT. It is turned on when thebattery is being re-charged. The gate of Switch2 is controlled by thecharge_bat_on signal. The logic for charge_bat_on is as follows:charge_bat_on=vchrg_higher AND mcu_charge_en AND in_reg AND[mcu_recov_bat OR bat_not_dead] vchrg_higher indicates that VCHARGE isgreater than VBAT. mcu_charge_en can be de-asserted by the MCU tointerrupt charging in order to perform an MCU initiated batterymeasurement using mcu_chk_bat. in_reg indicates that the Battery ChargerOutput (VCHARGE) is in regulation. bat_not_dead indicates that VBAT isabove the programmable Dead-Batt threshold. mcu_recover_bat indicatesthat the MCU wants Switch2 on—even if VBAT is less than the DeadBattthreshold, This allows the MCU to recover a dead battery.

Switch3 is the switch between VBAT and VSUPPLY. It is turned on when thesystem is being supplied by the battery and not the external charger.The gate of Switch3 is controlled by the vbat_on signal. The logic forvbat_on is as follows: vbat_on=implant_bat_powerup ORalarm_chk_bat_inprogress; alarm_chk_bat_inprogress indicates that analarm-driven battery check is being performed. implant_bat_powerupindicates that the battery is to power up the MCU, either to perform anAlarm-initiated initial power-up or to extend an Alarm-initiatedpower-up. implant_bat_powerup is defined as:implant_bat_powerup=vbat_to_mcu_req AND vbat_to_mcu_en. vbat_to_mcu_reqis the request to power up the MCU from battery. vbat_to_mcu_req isdefined as: vbat_to_mcu_req=[rtc_alarm OR mcu_vdd_on] AND bat_not_dead.vbat_to_mcu_en is the precondition for powering up the MCU from battery.vbat_to_mcu_en is defined as: vbat_to_mcu_en=NOT [charger_on].alarm_chk_bat_inprogress is generated in the Battery Monitor Controlblock. alarm_chk_bat_begin is defined as:alarm_chk_bat_begin=alarm_chk_bat_req AND alarm_chk_bat_en.alarm_chk_bat_req is generated by alarm to request a battery check.alarm_chk_bat_en is used to block alarm generated battery check requestswhen the MCU is powered up. alarm_chk_bat_en is defined as:alarm_chk_bat_en=NOT [vbat_to_mcu_req OR charger_on].

Switch4 is the switch between VBAT and the sensing circuitry within theBattery Monitor. The gate of Switch4 is controlled by the chk_bat_onsignal. chk_bat_on is generated by the Battery Monitor Control block. Itis triggered by either mcu_chk_bat or alarm_check_bat_begin, and stayson for the 30 msec battery monitoring cycle.

Switch5 is the VDD_PAD switch, which is between the internal ASIC VDDand the VDD pin, which supplies the MCU. Switch5 is needed because thebattery measurement requires a valid VDD for the ASIC, but the loadpresented by the MCU would corrupt the battery measurement. The gate ofSwitch5 is controlled by the vdd_to_mcu signal. The logic for vdd_to_mcuis as follows: vdd_to_mcu=NOT[alarm_chk_bat_inprogress].alarm_chk_bat_inprogress is generated in the Battery Monitor Controlblock. alarm_chk_bat_begin is defined as:alarm_chk_bat_begin=alarm_chk_bat_req AND alarm_chk_bat_en.alarm_chk_bat_req is generated by the Alarm Timer to request a batterycheck. alarm_chk_bat_en is used to block alarm generated battery checkrequests when the MCU is enabled. alarm_chk_bat_en is defined as:alarm_chk_bat_en=NOT [vbat_to_mcu_req OR charger_on].

The Battery Monitor Control circuit includes a state machine thatcontrols the sequence of events required for a battery voltagemeasurement via the Battery Monitor circuit. By default, the BatteryMonitor Control initiates a battery measurement every 90 minutes. Anun-scheduled battery measurement can also be initiated by the MCU bysetting the MCU_CHK_BAT bit in the PWRCTRL Register. The state machineuses the 100 Hz clock to produce the chk_bat_on and bat_mon_latchsignals required to enable Switch4 and the Battery Monitor circuit, andto latch the results of the battery measurements. A third signal,alarm_chk_inprogress is used in the Switch Control block to controlSwitch5—to keep the MCU load off of VDD when a battery measurement is inprogress.

The DFT Block provides digital test access to the Power Control andAlarm Timer blocks via the DTEST pin. The DTEST pin can be programmed tobe an input or an output by setting or clearing the DTEST_OEN(Output_Enable_Not) bit in the DTESTCTRL Register. When DTEST is anoutput, it can be connected to one of eight internal signals as definedby the lower 3 bits of the DTESTCTRL Register. One of the signals[cntr_q7_out] is the bit7 output of one of the 5 Ripple Counter bytes asselected by the lower 3 bits of the TSTCNTR Register, and enabled by theTST_CNTR bit of the TSTCNTR Register. When TST_CNTR is set, the 5 bytesof the Ripple Counter are clocked in parallel instead of in series, andclocked by SPI_CLK instead of clk100. In this mode, the 5 individualbyte outputs can be tested with a very short test duration. The othersignals that can be routed to DTEST are documented in the RegisterDefinitions section of this document. When DTEST is an input, it can beused as an alternate clock input for the Demodulator. The DFT Block alsocontains a test register [PWRTESTCTRL] that allows the tester to forcethe states of various Power Control signals. When bit7 of PWRTESTCTRL isset, the Power Control circuitry is connected to 6 other bits of thePWRTESTCTRL Register—instead of their normal internal ASIC signals. Thedetailed mapping of signals to register bits is documented in theRegister Definitions section of this document.

The Level-Shifters are required to interface digital logic signals thatcross boundaries from one supply domain to another. The ASIC includeslevels shifters for nearly every combination of supplies (VDD, VREG,VBAT, VSUPPLY, VCHARGE, VSTIM, PWRIN).

The Pad Ring consists of circuits and devices intended to protect theASIC from ESD events. For analog pins, the Pad Ring cells typically havea negligible effect on the function and performance of the circuit. Fordigital pins, the Pad Ring cells include the appropriate Input, Output,or Input/Output buffering, as well as the ESD protection. All of thedigital Pad Ring circuits include diodes connected between the pin andVDD_PAD and between the pin and VSUB. The analog Pad Ring circuitsinclude diodes and special ESD clamps between the pin and VSUB. Theanalog pins do not include diodes to VDD_PAD. The Pad Ring is intendedto meet the JEDEC standard for 2 KV Human-Body-Model (HBM) ESDprotection.

Charger

The Patient Charger communicates with and replenishes theMicrostimulator deep within the neck utilizing the near field effects ofan electromagnetic field. The Patient Charger is designed to be used byboth clinicians and patients. It consists of a coil that is run througha handle that separates to expand for placement over then head. Onceplaced over the head and closed the Patient Charger may attempt to findthe Microstimulator and start charging. When charging is complete thepatient may be signaled. FIGS. 31A and 31B illustrate one variation of acharger (which may also be referred to as a patient charger or anenergizer). In use, a clinician may program the microstimulator byconnecting a USB cable between the Prescription Pad and the PatientCharger. The Patient Charger wirelessly connects with the implant andwith outer devices (e.g., the controller such as a prescription pad).The Patient Charger may also record all charging sessions and storeMicrostimulator data.

The chargers described herein are configured and optimized for use withthe cervical, low duty-cycle microstimulators described above. Thus,these chargers have many advantages over any prior art systems. Inparticular, these charges may be worn about a subject's neck and mayvery quickly charge the implanted microstimulator, and may program andcontrol the microstimulator as well as receive data or information fromthe microstimulator. The chargers described herein may use a solenoidthat connects around the subject's neck with novel connection mechanism.For example, the connection mechanism may be clasp or quick connectconnector that connects the loop (coil) of the charger around thesubject's neck. The quick connector may be magnetic or friction fit. Forexample, in some variations the connector closing the loop around thesubject's neck includes insertion of pins to connect one side of theloop(s) with the opposite side. For example, in some variations, thecharger (e.g., energizer) coil uses a breakable coil with a magneticlatch and pogo spring pins to make contact. The coil resistance may bekept low despite the clasp/connection. For example, a multiplicity ofpins may be used to keep coil resistance low and Q high.

In some variations, a high-efficiency class-D amplifier may be used todrive coil reliably. A variable frequency may be used to maximize powertransfer and may be tracked with a control loop. In some variations, avariable inductor that uses DC flux to vary coil permittivity may beused to tune the coil to maximize transfer. In some variations, ameasure of back telemetry modulation depth allows closed loop control ofthe magnetic field to optimize power transfer, avoid Microstimulatoroverheating, and avoid saturation of telemetry communications.

The magnetic field strength of the charger may be modulated via adigitally compensated pwm circuit so that the power is critically tunedrather than using a resistive element. In addition, the carrierfrequency may be generated using a phase accumulator to provide highlyaccurate frequency generation for precise tuning.

The Patient Charger may be stored in a Charging Dock to keep the batteryin a charged state. A travel wall socket adapter may also be used. TheCharger typically includes a battery, such as a LION rechargeablebattery.

In some variations (such as that shown in FIGS. 31A and B, the chargerincludes a handle region 3105 and a loop region 3103. The loop region isconfigured to encircle the patients neck, and may be expanded by openingthe handle, as shown in FIG. 31A. Once over the patient's head andaround the neck, the handle may be closed, as shown in FIG. 31B, andready for activation to charge and/or communicate with the implantedmicrostimulator. The Patient Charger may be configured so that it doesnot communicate or charge the Microstimulator while the handle isopened. Operation may start once the handle is closed. FIGS. 31C and 31Dshow one variation of the coil contraction for chargers that includeloops that open to fit over the subject's head and close around the neckto charge (“coil contraction and expansion”). In this example, coilcontraction is achieved using coil wires and a shroud that can take manycycles of repeated coil opening and closing while maintaining the coilshape. The “arms” shown in FIGS. 31A and 31B are not shown in FIGS. 31Cand 31D, but instead the body of the implant may be adjustable (e.g.,like a bolo) to shorten the length of the coil. In some variations thebody or handle region may slide up the coils after they are positionedaround the neck (e.g., FIG. 31C), and slide back down to open the loopup again for removal over the head (FIG. 31D). In other variationsdescribed below, the charger may be opened and closed on one or moreends or sides to place it around the subject neck like a collar.

In operation, the Patient Charger typically develops an axial magneticfield in alignment with the Microstimulator in the neck. The loop issized to accommodate the largest neck and provide sufficient power tocharge the battery in the adjustments to assure that sufficient chargeis being transferred to Microstimulator.

Recharge time for the Microstimulator may be dependent on how muchenergy is drained between recharges by the patient. This may depend uponthe patient settings and how often the patient charges. Patients may beable to charge as infrequently as every month. This may allow theclinician to recommend a charging schedule that is most convenient forthe patient; such as when a care giver is available. The neck loop makescharging a hands free operation once the device is put around the neck.

The operation of one variation of a charger is described in the contextof the state diagram shown in FIG. 32. Other variations may include someof these states, or different states; the example shown in FIG. 32illustrates just one embodiment of operation of a charger. Thewhite-colored states indicate that the Patient Charger is acting alone,the shaded states are when the Microstimulator is locked to the PatientCharger. The states described below may be included.

The DOCK state occurs when the Patient Charger is in Charging Dock andis replenishing, or finished replenishing its own battery.Microstimulator charging is not permitted while in the Charging Dock.

The iSEEK state (or Implant Seek state) occurs when the Patient Chargeris out of the Charging Dock and the handle is closed, the PatientCharger automatically starts searching for the Microstimulator (iSEEK)for 60 seconds. Once the Patient Charger detects the Microstimulator,has supplied enough energy to start charging, and established a qualitycommunication link, iCHRG mode is entered. The patient can use theCharging button on the Patient Charger to retry searching or stopsearching.

The iCHRG state (or Implant charging state) is started once the PatientCharger has linked to Microstimulator and the Microstimulator hasstarted charging its internal battery. Once charging is complete, andthe battery is topped off, STBY mode may be entered. Normal charge isindicated by a Green light on the Charging button, completion of toppingoff is indicated by a blue light. Topping off the battery occurs whenthe Patient Charger is left on the neck beyond the normal charging time.This is an optional patient has each time he or she charges theMicrostimulator, and takes much longer than normal charging.

The Charging state may only start when the Microstimulator Battery isabove the ‘reversible’ battery voltage and the Charger itself hassufficient charge. If the battery has dropped below the ‘reversible’voltage the manufacturer may be contacted for further assistance andreimplantation may be required. During Microstimulator charging, theMicrostimulator RTC may be synchronized to the crystal controlledPatient Charger RTC. The Microstimulator event logs may also be uploadedto the Patient Charger. The Patient Charge keeps a complete history ofall events that were recorded on the Microstimulator.

The iPROG state occurs if the Prescription Pad is connected to thePatient Charger the Clinician may perform many operations including:Microstimulator Charging, Programming, Diagnostics, and Firmware Update.Some of these operations may require a non-interrupted link and may berestarted if there is an interruption. The Clinician may be notified ifthis is the case. The Microstimulator may continue to charge during thisoperation. The system may stay in iPROG until the Prescription Padspecifically disconnects.

The iSTBY state occurs after the Patient Charger has completed chargingthe Microstimulator but has not been put back into the Dock.

The SLEEP state occurs when the Patient Charger is not docked or in use.The charger may be put into a very low power (sleep) state when only theRTC is active. The RTC is typically always active.

The SETUP state occurs when the user is changing the Patient Chargeroptions on the LCD screen.

FIG. 33 illustrates one variation of a functional diagram of a charger.In this example, the charger includes a plastic cover that may cover allmetal parts electrically isolated from the user. As described above, theantenna may be sized to fit the largest neck size of 50 cm circumference(≈16 cm diameter), and the largest head size of 63 cm circumference withsome allowance for hair with a target of 72 cm circumference (≈23 cmdiameter). It is assumed that the closed loop size of 15.5 cm may beused on even the smallest neck. Loop power may be sufficient to chargethe Microstimulator up to 45 degrees out of alignment. The weight of theassembly may be minimized and no greater than a few pounds (e.g., lessthan 1 pound, less than 0.5 pounds, less than 0.25 pounds, less than 0.1pound, etc.). The device may be dust and water protected.

In FIG. 33, the system control includes a charging/display Controllerthat may be control overall function of the Patient Charger. An externalcontroller (e.g., Prescription Pad) can send requests to the PatientCharger wirelessly or thorough a wired connection (e.g., through a USBor Bluetooth interface). In some variations, communications with theMicrostimulator may be through an RS-232 Interface operating a 4800 bpsbaud and the frame may be configured as follows: 1 start bit, 8 databits, 1 even parity bit and one stop bit. The UART may have the abilityto detect overruns, noise, frame, and parity errors. The Patient Chargermay be able to reload the entire Microstimulator code image over thePower Transceiver. (Additional error coding is disabled during thisoperation so the code image may be checked after load).

Data to the Microstimulator may be encoded to withstand single, doubleand burst errors. The error rate signal may be available for use by thePID controller. The controller may also include a Power Transceiver thatprovides charging power to the Microstimulator in a predeterminedfrequency range. The frequency and tuning of the Transceiver aretypically controlled through a proportional integral derivative (PID)control loop feedback. The Power Transceiver may have a CouplingStrength signal that indicates the coupling coefficient between theMicrostimulator and the Patient Charger. The Collector Voltage on thePower Transceiver may be set through the Boost Converter. The boostconverter may be controlled by the CPU and may produce volts and ampsand may have a predetermined startup time (Z). The temperature of thecoil may be monitored and may be shut down if the temperature increasesmore than 2 degrees centigrade over ambient.

In some variations, the loop (Charger Coil) of the charger may have anaverage closed diameter of approximately 16±1 cm. In variations in whichthe loop is expanded to fit over the patient's head, the average opendiameter may be approximately 23±2 cm. The loop may be made of anyappropriate material for transmitting power to the implant (e.g., byinduction). For example, in some variations, the loop comprises turns ofgauge-stranded wire with mil thick insulation. A shroud may cover thewire bundle.

As mentioned, the battery in the charger may be a rechargeable lithiumION battery, which may provide enough power for 1 hour ofMicrostimulator charging between charges of the charger itself. The LIONbattery may be protected by a thermal switch, and the LION battery maybe disconnected when the voltage drops below TBD volts. The LION batterymay be charged through a 5V power plug and may charge within 2 hours.The primary internal power supply fed from the LION battery may be 3.3V.

In some variations the charger also includes a display or output. Forexample, an LCD screen may provide information to the user on a 96×96bit graphic monochrome screen. One or more inputs or controls may alsobe included. For example, four buttons may allow the patient the abilityto set Patient Charger functions. A Charge button may allow the user tomove the Patient Charger back and forth between Stand-by andMicrostimulator charging and the charger may show the status ofMicrostimulator battery charging. A color-indicator may indicate chargestatus by color coding (e.g., Blue, Green, Yellow or Red). In somevariations a speaker may provide audio cues and have 5 volume levels. Inaddition, an optical or mechanical switch may indicate that the handleis open or closed in relevant variations of the charger.

For example, FIGS. 34A-34D illustrate various exemplary display screensthat may be used with the chargers described herein. For example, inFIG. 34A, the display screen (e.g., an LCD screen) provides informationto assist the patient and clinician in maintenance and programming of animplanted microstimulator. In FIG. 34A, the setup buttons A-D are shownalongside the screen and the Charge button is shown below the screen.

The charger may indicate the mode or status (e.g., “DOCK Mode” when thecharger is in the dock or plugged into an AC Adapter, etc.). The chargermay display the time (in 12 or 24 hour mode) and indicate that day lightsavings time is set (DST). The date shows the month and day, the year isonly shown during setup, and it may also indicate the time zone with arepresentative city. The Charger battery status indicates the chargestatus of the Patient Charger. A symbol (such as a lightning bolt) mayindicate whether the battery is charging and only may occur when theCharger Mode is in DOCK and the AC Adapter is connected. Charger audiotypically indicates the level of acoustic feedback given to the user. InFIG. 34A it is shown muted, but different loudness levels arerepresented by 4 different speaker sizes. A charge alarm may be set as areminder to the patient to charge there system from the PrescriptionPad.

When the charger is in the iSEEK mode (e.g., when the Patient Charger isaround the neck and ready to charge, e.g., with the handle closed,and/or when the CHARGE Button has been pressed), the display may besimilar to that shown in FIG. 34B. In this example, the screen color isinverted to indicate a Microstimulator Operation, the Patient Chargerstatus is displayed (iSEEK), the implant present symbol (shown as anoutline of an implant) and the ‘Locking’ implant status is shown whenthe coil has detected the presence of the Microstimulator but has notstarted charging.

FIG. 34C shows an example of a display on the charger when the device isin the iCHRG mode (when the Microstimulator starts charging). In thisexample, the Battery Charging symbol may appear inside the Implantsymbol. The Implant Battery Status is shown with both a numeric and agraphical display of battery charge level. The numeric charge level maygo over 100% when topping off the battery. The charging symbol (e.g.,lightning bolt) appears when the device is charging and is synchronizedto the Charger button LED. As mentioned, the Implant Battery Levelindicates the implant battery level. 75% charge is considered a fullcharge, so the charging indicator may stay energized for 60 secondsafter a full charge is indicated.

FIG. 34D is an example of a display from the charger when it is in theiPROG mode when an external controller (e.g., a Prescription Pad) iscommunicating control instructions to the implant through the PatientCharge. The state of the battery is independent of iPROG. FIG. 34Eillustrates one example of a display screen when the charger is in aStandby mode (e.g., after charging and programming is complete). Anemergency shutoff display is shown in FIG. 34F. In some variations, themicrostimulator can be turned off by pressing all 4 buttonssimultaneously for 30 seconds; the patient may also be asked to push asequence of buttons to verify that the patient wants to turn the deviceoff. Once the implant is turned off it can only be turned back on by theClinician. The charger may display when the implant is in an off state,as illustrated in FIG. 34F.

The charger may receive information from the implant and/or from anexternal controller (e.g., prescription pad). The charger may pass alonginstructions to and collect data from the microstimulator. For example,software of firmware may be downloaded into the Microstimulator from thecharger when commanded from the Prescription Pad, and data may beuploaded from the Microstimulator when commanded from the PrescriptionPad. In some variations, the charger may be updated or restored by thePrescription Pad when the Charger is put into a “boot” mode.

The charger may generally include a microcontroller having a CPU, clock,RAM, EPROM, ADC (receiving/regulating battery voltage, ambienttemperature, coil temperatures, and transmitter coupling strength). Themicrocontroller may also boost supply control signals and stepper motorcontrol signals.

In general the charger may interface with an external controller such asa prescription pad. The prescription pad may include software, hardwareand/or firmware for controlling the operation of the implant and/orcharger. The charger may serve to relay instructions (and receive data)to and from the microcontroller implant and the controller. For example,a controller may regulate the dosing from the implant. FIG. 35A showsone variation of a dosing management control screen that may be used toset the dosage level (and interval) for the microstimulator implant.Although the variations described herein typically use a separateexternal controller, in some variations the external controller and thecharger may be integrated together into a single device.

In FIG. 35A, the control screen shows a tool bar that allows for anincreased/decreased dose to be selected, and allows for more than one(e.g., four) sequential doses to be added. The screen also includes Backand Forward buttons to allow toggling between different doses. Theactive dose is highlighted and selected when the screen comes up. Whenmultiple doses are displayed the dose may be selected by clicking orusing the back and forward selector arrows. A Test Dose control may alsobe included, which may allow stimulation with the selected dose for 1, 5or 60 seconds with the selected program. A key (e.g., space bar) canimmediately stop the stimulation. The Stimulate button turns green ifstimulation is successfully, yellow if current sources are out ofcompliance, or red if stimulation cannot be delivered. The Impedancevalue is updated when Stimulate is pressed. Various icons may alsoindicate the status of one or more components (including themicrostimulator and charger). For example, a charger icon may indicatethat the charger is connected and operating with sufficient batterycharger. If the battery is to low an icon may indicate the condition,and it may not be usable. Text may be shown, as well as a colored barindicating the state of the battery (<10% is red, <25% is yellow,otherwise it is green). A person icon may indicate that aMicrostimulator was found and identified on the patient, and in somevariations may display the serial number of the implant. If amicrostimulator is not found the person icon is grey, and if an issue isidentified with the microprocessor an error icon may be shown

The electrode impedance of the microstimulator may also be displayed.For example, the electrode impedance shown may be the last impedancetaken, and it may be updated when a connection is established to themicrostimulator or before a test stimulation. This value it can bemanually refreshed. The screen may also show the current level (A) inmicroamperes and typically ranges from 0 to 5000 in 25 uA increments.The timing (S) in seconds typically indicates the duration the stimulusmay be on during each dosage ranging from 1 to 1000 seconds (e.g.,default: 60). The (Pulse) icon allows the pulse waveform to becustomized. Pulse (F) times per second sets the frequency of the pulsetrain between 1 and 50 Hz (default: 10 Hz). The pulse width (PW) inmicroseconds is the pulse width generated in microseconds and rangesfrom 50-1000 uS (default: 200 uS) in 50 uS intervals. In general, valuesmay be entered and then tested with the Stimulate button. The Stimulatebutton turns green if stimulation is successful, turns yellow if currentsources are out of compliance, and turns red if stimulation cannot bedelivered. The Impedance value is updated when Stimulate is pressed.

In some variations the system stores the patient history, which mayinclude a listing of all doses executed, and the impedances at the startof a Dosing program (only the first dose of a program). The list can besaved or appended to an existing file that is stored under theMicrostimulator Serial Number. When appending a file, duplicates may beeliminated. This history may be kept internally, or it may betransferred for analysis or storage. For example, a history file can betransferred to a server for recoding in a patient's medical records.

Additional (e.g., “advanced”) parameters may also be regulated orcontrolled. For example, an advanced Impedance Screen may allow aclinician to modify impedance parameters to debug electrode problems.For example, FIG. 35B shows a control screen for setting advancedparameters. In this example, the access impedance is measured at theleading edge of the pulse, the total impedance is measured and the endof the positive pulse. Amplitude can be adjusted in 25 uA steps. In thisexample, the pulse width can be modified in 50 uS steps. The number ofaverages can be set to reduce measurement noise in increments of 1.

The systems described herein may also include diagnostics for diagnosingproblems with one or more components. For example, the system (e.g.,external controller) may display a diagnostics screen that shows keyparameters and allows Self-Test and Firmware updates. FIG. 35Cillustrates one example of a diagnostics screen. In this example, thescreen displays the serial number of both the Charger and Implantpresented (if none are present the clinician may be asked for theinformation). The screen also shows an IDA and IDB number (electronicreadable IDs), date and time information, temperature information (e.g.,the temperature of Charger Coil and Implant Microprocessor), listfirmware/software versions, indicate the battery voltage from bothunits, indicate the received telemetry signal strength from both units,and execute a self-test from both units (and display the results of theself-test).

Example 2: Charger

One variation of a charger (referred to herein as an “energizer”) isdescribed in FIGS. 36-43. In this example, the energizer for poweringand programming the microstimulator attaches around the patient's necklike a necklace or collar. FIG. 36A shows one variation of the energizeraround the subject's neck. In this example, about an average of 20seconds of charging will be required per day for NCAP treatment using animplant as described above, and it is recommended that the patientcharges at least every week (e.g., for approximately 20*7=3 minutes),even though it is possible not to charge for up to a month requiring a20-30 minutes to charge.

In this example, the Energizer consists of 4 components: Coil andMagnetic Coil Connector Assembly, Electronic Module, Battery Module, andAcoustic Module.

FIG. 37 shows one variation of a coil and magnetic connector assembly.In this example, the Coil is 13 Turns of a bundle of 26 gauge magnetwire (N conductors) spaced at 100 mils. The connector uses spring loadconnectors, 2 per connection (20 milliohms per connection) and goldlandings resulting in 130 milliohms. The Inductance is around 40 uH andQ is over 200. The battery module in this example is a 650 mA/hrLi-Polymer battery with a built in temperature sensor. It is attached tothe coil assembly and connects to the Electronic Module with 3 flexiblewires. The charge and discharge rate is 1C. The charge rate may beslower than one hour depending due to thermal protection. The batteryback is packages in a plastic container that is 5.8 mm×42 mm×34 mm.

An acoustic module may include a 16D×2.5 mm speaker that can generate 82dB SPL above 500 Hz.

In operation, an Energizer creates a magnetic field of approximately47-94 A/m (0.6-1.2 Oe) at a frequency between 127-135 KHz. This lowfrequency range was chosen for several reasons: 1) it is acceptable toradiate in the range in most countries around the world, 2) staying withradiated limits biologic limits is possible, 3) absorption by the humanbody is minimal and field penetrates with minimal attenuation, 4)conductive materials block the field has less of an effect, 5) highefficiency electrical circuits are easily achieved at lower frequencies.The primary disadvantage of lower frequencies is that a higherinductance resonator coil is required in the body.

The magnetic field may be generated by clocking the transmitter at thecarrier frequency (CF) at the system resonant frequency. The collectorvoltage (CV) may be set to provide sufficient power to energizeMicrostimulator coil to charge battery and power MCU, but it does notnecessarily directly indicate voltage induced in implant. The CV mayalso be set to allow various positions on neck and movement, and tocompensate for energy loss due to Forward and Backwards telemetry.Finally, the CV may be set so that it does not overpower and causeexcessive Microstimulator heating.

At least two charging coil schemas may be used: a solenoid and a pancakecoil. A solenoid was chosen due to the required implant depth ofnormally around 2-5 cm. A solenoid generates a fairly uniform field andmakes positioning of the coil unimportant. A pancake coil would requireprecise positioning and excessive power to reach coil to coil spacing inexcess of 2 cm. The challenge with the solenoid was to find a systemthat would be comfortable for the patient. That was achieved by using amagnetic spring loaded connector, and the system is further aided by thefact that charging times are very short, never more than 20 minutes, butusually less than 1 minute.

The Energizer and Microstimulator coils may be tuned to resonate so thatenergy is transferred with the maximum efficiency from the Energizer toMicrostimulator. The Microstimulator in turn harvests the energy fromthe Energizer created magnetic field to power itself. The powerharvested is less than 15 mW. FIG. 38 shows a schematic diagram of thetransfer of power between an energizer and a microstimulator. Tuning, ormaximizing the mutual inductance between the two coils may be performedby using resonators that are physically adjusted to approximately 133KHz±4 KHz. Fine tune adjustments may be made dynamically by varying theEnergizer frequency with the allocated 127-135 KHz frequency band.Another method to be employed for electronic tuning that may be usedinduces a static flux in series inductor in the Energizer coil toelectronically modify the inductance (see, e.g., U.S. Pat. No.3,631,534).

Energy transfer is controlled by throttling the magnetic field. Themagnetic field is typically created by a high efficiency Class-Damplifier. The induced coil voltage on the resonator is controlled bythe collector voltage driving the amplifier. It is important to onlyprovide sufficient power to the implant as not to saturate theMicrostimulator circuits or overheat the Microstimulator, a conditionwhich can easily be achieved. Energy transfer varies significantly withvertical position so feedback is required. Feedback is obtained throughtwo mechanisms, the most obvious being to query the Microstimulatortelemeter incoming energy level, a much less obvious method thatmeasures the difference in Energizer coil voltage between the presenceand absence of the Microstimulator. With that measure the energy beingabsorbed by the Microstimulator can be calculated with sufficientaccuracy to control the Energizer collector voltage.

The telemetry system in this example is implemented that two standardmicroprocessor UARTs communication with a RS-232 type half duplexprotocol where the Energizer is the master. Two rates 1200 and 4800 baudmay be implemented. Forward telemetry modulates the transmittercollector voltage to send data across. To keep the Microstimulatordemodulator as simple as possible a DC balanced Manchester code may beemployed with a simple zero crossing data slicer. The RS-232 code itselfdoes not need to be DC balanced, but the presence of start and stop bitsare sufficient to allow sufficient energy transfer duringcommunications.

The Microstimulator resonated may be put into one of two states with ashorting switch. When the switch is open the Microstimulator isoperating normally, receiving power and telemetry, and is loading theEnergizer. When the Microstimulator switch is closed the coil is nolonger tuned to the Energizer coil and the Microstimulator ceases toreceive power, and the load that the Microstimulator normally asserts onthe Energizer is removed. This switch provides several functions: it maybe used to send back telemetry data to the Energizer, used by theEnergizer to measure the power absorption by the Microstimulator, and/orused by the Microstimulator to turn off power absorption in case theMicrostimulator becomes too hot or the internal voltage becomes toohigh.

The Microstimulator may respond to all packets by toggling the loadswitch with the UART. Data is sent in NRZ format (e.g., back telemetry).The Energizer may measure the coil voltage, removing the ≈130 KHzcarrier and extracting the resulting data stream that is effectively thepeak coil voltage updated at a rate of 20 KHz. The Energizer convertsthis analog voltage into a digital word and slices the data to producebits that are fed to the UART. This is done in the digital domainbecause a sophisticated min/max peak detector can be implemented thatdoes not require DC balanced data and can respond within 1-2 symbols.

Power is adjusted by achieving a target modulation depth on receivedback telemetry data. The target modulation depth is determined bycalibrating the system through measurements of power transfer to theMicrostimulator. It is unknown at this point when calibration willoccur: once for all systems, once for each system, on power up of eachsystem, continuously as the Energizer coil moves around.

Recall that an electronic module with the battery module is shown inFIG. 37. The electronic module in this example is 1.5 tall by 1.8 wideand connects to the coil. It is attached to the coil with two flexiblewires.

The module may have a custom LCD for displaying time and alarms. A ModeSwitch (SW3) may be used, e.g., in the upper left corner, along with UPand DOWN switches (SW2 & SW1). A MicroUSB port with charging LED (D2)may be in the lower left. A RGB LED may be on the right side just belowthe LCD and a light guide will route the light to a visible band calledthe light bar.

As mentioned, the energizer example described may also include a patientcharger RF interface module. For example, the energizer may communicateto the Microstimulator through an RF Interface. The RF Interfacetypically receives serial NRZ data from the MCU UART, converts it toManchester code that modulates the coil to power and communicate withthe Microstimulator. When not transmitting data or idles the RFInterface receives data from the Microstimulator. This data is receivedin an Analog form and is sent to the MCU ADC where it is sliced and fedinto the MCU UART. The MCU is responsible for setting the RF Interfacepower level and the frequency of operation.

The MCU in this example operates as a master sending packets to theMicrostimulator and expecting response within an allocated period. ThePacket protocol contains preambles to synchronize communications anderror checking to assure that data is reliable. MCU generates serial NRZtransmission to the RF interface and is responsible for: insuringcontiguous bits/words in a packet so as not to disrupt the Manchesterreceiver at either 1200 or 4800 baud; and/or maintaining a high statewhen not transmitting; maintaining somewhat constant power (e.g. whenidling sending alternating data rather than long blocks of idlecharacters.

The MCU receives filtered analog data that represents the RF carrierlevel and converts it to digital data for: slicing data when return datais expected, to extract serial NRZ data that is presented to the MCUUART for decoding; monitoring modulation depth of returning data toestimate and optimize the power level sent to the Microstimulator (poweris optimized to provide sufficient power to charge battery but not toover-heat Micro stimulator); and/or monitoring coil voltage levels toverify expected coil voltages and assure system is operating correctly.The MCU may also program the RF Interface to modulate either carriermodulation or collector voltage modulation or both, and the MCU mayadjust the carrier frequency to maximize the mutual coupling between theEnergizer and Microstimulator resonators.

The RF Interface section consists of functionality implemented by MCUhardware and software, Programmable Logic Device (PLD), and analogcircuitry. The functional block diagram is shown in FIG. 39.

In operation, the MCU generates NRZ data from USART3 and from TIM3_CH3 aclock that is within 1% of 16× the baud rate. The Manchester Encoderconverts this NRZ data to Manchester data (MTX) resynchronizing to thestart bit every word. As soon as start bits enter the Manchester Encoderthe (RX/TX) bit goes high and stays high until the last stop bit issent. The RX/TX bit uses two multiplexers to select either the pwmRCduring receive mode and the pwmTXL or pwmTXH during transmit mode tofeed to the Pulse Width Modulator (PWM). The PWM uses these values todrive the High and Low switches to generate the collector voltage. Whentransitioning between these pwm values digital Q compensation smoothsthe transitions utilizing a digital filter to control the overshoot andundershoot reducing extraneous frequency components.

The RF Tuning Algorithm adjusts Phase Accumulator to generate a carrierfrequency with 5 Hz resolution programmed with the 16 bit M register.The RF Tuning Algorithm has not been determined but most likely uses ameasure of modulation depth from the Digital Slicer. TheModulator+Deadtime logic drives the High and Low Switches in theH-Bridge configuration to excite the coil. 1/MCO of deadtime is insertedto avoid current waste through simultaneous activation of the High andLow Switches. If the MCU has programmed the GatedMod bit then the MTXbit gates the carrier on and off assuring that switching occurs on theedges.

The voltage is measured across the coil and the carrier is extractedfeeding an analog signal to the ADC with a bandwidth of less than 20KHz. A digital slicer is implemented in software that slices the signalwith the short term average of the signal allowing USART synchronizationwith a minimum number of preamble characters in the response packet. Theshort term average is determined by minimum and maximum peak detectorsthat are reset at the symbol rate and smoothed appropriately.

The Class-D amplifier and the back telemetry data detector is shown inFIG. 40. An H-bridge topology is implemented through PMOS (Q3 & Q5) andNMOS switches (Q4 & Q5). These switches are driven by a PLD implementingthe logic described earlier. The coil is connected through two seriescapacitors C30 and C36 surrounding a coil. Zener diodes prevent the coilvoltage from exceeding+/−80 volts. VT is the so-called Collector Voltageand 1V generates around +/−50V on the coil.

VT is generated using a PWM converter shown in the following diagram ina very efficient manner. The PMOS and NMOS switches are driven by thePLD and VT is modulated with data. The carrier frequency for thiscircuit is 500 KHz about 4× higher than the RF carrier frequency.Referring to FIG. 40, the data detector is implemented by measuring thevoltage across the coil with a difference amplifier implemented by U11B.The LT6621 has a 50 MHz GBW product which is able to track coilmodulation on the 135 KHz carrier with little loss of fidelity. Thevoltage is divided by 1000× to scale the +/−80V range to the +/−3.3 voltrange of the system. After the voltage difference is obtained D11 & C53rectifies the waveform and U11 A implements a 2 pole 20 KHz low passfilter prior to ADC conversion. Due to the very high Q of the coil theactual frequency content of the signal is much less than 20 KHzpermitting slower ADC conversion rates.

As mentioned briefly above, the energizer user interface typicallyconsists of a Clock LCD display, Up, Down and Select Keys for settingthe time, Alarms, and Emergency Microstimulator off. In some variationsthe display includes a multicolor LED indicating the state of charge ofthe Microstimulator. The LED may indicate that the Energizer is pluggedinto a USB power adapter or port and is charging. A speaker may beincluded to provide charging cues to the patient.

For example, the charger may include an MCU LCD controller that is usedto control the time display.

As mentioned, the power system for the energizer (charger) may includean MCU. The MCU is typically always powered, even when the battery dropsbelow 2.5V. Peripherals are enabled through VCCEN. The target operationof the circuitry is 3.3 Volts. It is the responsibility of the MCU tonot let the battery drop below 3.4 volts. When the RF Interface isoperating it can require up to 500 mA. This will limit the batterycapacity to around 90% of what would be possible with a lower operatingvoltage.

Battery charging may occur through a MicroUSB port. The input isdesigned to be operated at 5V but can tolerate 30V. Charging will occurwhen the port is between 4.5-6.4 volts. An AC adaptor or USB cable to aUSB device can be used for charging. If hardware detects a USB sourcecharge will be limited to 100 mA not to pull down the USB device,otherwise charging can occur at full rate. There multiple temperaturecontrols to avoid skin exposed surfaces from exceeding 41° C. whileoperating at 25° C. Table 8 describes some of the temperature monitorsthat may be included as part of the system.

TABLE 8 Monitor Function Limitations Battery Protects battery Thermistorfrom damage by limiting charge rate per JEITA standards. ChargerProtects circuits Junction from damage Temperature by limiting chargerate. Sensor External Software periodically Will not completely stopCharger senses to limit charging. If charger is left in Temperaturecharge rate when hot location for charging it Sensor possible skintemperature will still charge reaches 41° C. Since MCU at a slow rate.does not control charging The device can be in an temperature is alwaysenvironment where monitored. Software even slow charging can controlsfast cause the charging through temperatures to rise beyond BATSET.desired levels. Even though the system will not power it is theresponsibility of the user to check the device temperature beforeapplication. System Level Software will monitor both The device itselfcan be left Temperature the External Charger in the sun, be applied, andSensor inside Temperature and MCU cause burns even without MCUtemperature to assure that being powered. It is the temperatures areresponsibility of the user to within range check the device beforeMicrostimulator temperature operations are enabled. before application.

In Table 8, BATSET=Float allows the charger to charge at fast rate ifall conditions are met, BATET=Low forces the charger to charge at slowrate; and BATSET=High allows charge to charge at fast rate if allconditions are met.

Closed Loop Vagus Nerve Stimulation

While the methods, devices and systems for treating chronic inflammationby modulating the inflammatory reflex have been described in some detailhere by way of illustration and example, such illustration and exampleis for purposes of clarity of understanding only. As mentioned, any ofthe system, devices and methods described above may be adapted asillustrated in all or some of FIGS. 41-57 to include sensing of vagalactivity and/or incorporate of sensed activity in closed-loop (or hybridclosed/open loop) stimulation of the vagus, e.g., to treat inflammation.

Sensing and closed loop control may be active or passive. Activesensing/closed-loop control may refer to sensing a predetermined timeafter stimulation of the vagus. Passive sensing may refer to sensing(and subsequent closed-loop control) that is not tied to stimulation.

FIGS. 41A and 41B illustrates that repeated vagus nerve stimulation mayalter the immunological setpoint in an adaptive fashion over time,meaning the effect on the inflammatory pathway may be reduced, as shownby the reduced reduction in TNF levels with subsequent stimulations. Theaccommodation or adaptation may also be patient-specific, with somepatients exhibiting greater adaptation or earlier adaptation than otherpatients. Chronic VNS may result in tachyphylaxis of the cholinergicanti-inflammatory pathway. In other words, overstimulation may result inloss of efficacy. Tachyphylaxis may be prevented or reduced byaccounting for accommodation to the new immunological setpoints. Forexample, the stimulation timing can be varied for subacute implantationsto chronic implantations. To assess the effect of varying thestimulation time, the vagus nerve activity can be recorded and theimmunological endpoints can be assessed. The delivery of electricalstimulation to treat disease can be called an electroceutical. Closedloop electroceutical VNS systems may be particularly suited for thetreatment of chronic inflammatory diseases, such as collagen inducedarthritis, inflammatory bowel disease, and metabolic syndrome, forexample. Implementation of a closed loop system and method may beginwith characterizing the vagal neural signatures in the chronic diseasesto be treated, initially in an open loop manner while treating withtimed electrical stimulations. Once sufficient vagal signatures areacquired that allow the system to determine the disease state and/or alevel of the efficacy of the VNS treatment, the treatment can be shiftedto closed loop VNS.

For example, the vagus neural response due to inflammatory stimulus canbe characterized, and the altered vagus neural response due to VNS canalso be characterized. Inflammatory stimuli include endotoxin,cytokines, live bacteria, which can be used to challenge the patient ora test subject, or can be the result of an infection or disease state.This can be done using a single channel device and approach, or using amulti-channel device and approach.

FIGS. 42A and 42B illustrates that there may be a potential to elicitresonance in the inflammatory reflex signaling pathway from VNS. Asillustrated, a single suprathreshold VNS pulse can activate theanti-inflammatory response. One chart shows that a single pulse achieveda similar reduction in TNF levels as a 600 pulse stimulation and a 3000pulse stimulation, and another chart shows that a single pulse was ableto dramatically reduce the lesion area in a rat model.

FIG. 43A provides an overview of the system, which is also described infurther detail above. The system can include an implantable stimulatorthat includes a POD and a microstimulator or microregulator that can bedisposed within a cavity within the POD such that the microstimulator isin electrical communication with the nerve. An energizer can charge themicrostimulator battery by RF induction and can also provide a telemetryinterface with the implant, thereby facilitating communication with themicrostimulator. The energizer can also interact with a prescription padwirelessly, such as by Bluetooth. A physician or other health careprovider or the patient can control, program, adjust, and/or monitor theimplant using an application on the prescription pad, which can be aportable tablet computer, a smartphone or other computing device. FIG.43B illustrates the method by which a POD can be secured over a nervewith the microstimulator. The POD can be squeezed open end to end suchthat the nerve channel is exposed to the nerve. The nerve can be placedin the nerve channel and the POD can be allowed to relax, during whichthe channel will conform itself over the nerve to secure the nervewithin the POD. The microstimulator can then be dropped into a cavity inthe open POD and over the nerve such that the electrodes of themicrostimulator are in communication with the nerve. The POD can then beclosed. A suture can be used to securely fasten the POD closed aroundthe nerve and microstimulator.

The system can be adapted and optimized to treat a variety a diseases inwhich the inflammatory response is implicated. For example, thestimulation parameters of the microstimulator can be optimized forrheumatoid arthritis and Crohn's disease. The stimulator can beprogrammed to deliver one or both type of stimulations, depending on theneeds of the patient. As further described herein, the microstimulatoroperation can be closed loop using either or both passive and activeneurogram sensing, and/or it can be open loop.

An open loop dosing or stimulation regime can include delivery ofstimulations according to a prescribed or predetermined schedule. Anyappropriate endpoints, such as changes in clinical manifestation ofdisease, changes in whole blood response to immunological challenge, orphenotypic or expressional changes in circulating lymphocytes ormonocytes, can be used evaluate the efficacy of the stimulation. Aclosed loop dosing or stimulation regime can include delivery ofstimulations on a schedule, which may be predetermined but alsomodifiable, and modifying the delivery of stimulations by passive oractive sensing of various signals, such as electrical signals of thevagus nerve, electrical signals from the heart, other nerves/ganglia,respiratory signals, etc. Sensing may be done using a sensorincorporated with the microstimulator apparatus, and/or with additionalsensors. Passive sensing can include periodic spike count sampling of atarget nerve, such as the vagus nerve, in order to determine vagus nerveactivity. Active sensing can include recording and evaluating an evokedneurogram in the vagus nerve, which can be accomplished by delivering astimulus impulse to the vagus nerve with the microstimulator and thenfollowing the stimulation by sensing the electrical activity in thevagus nerve, other nerves, and/or other tissues for a duration, whichcan be predetermined.

In general, the sensing may be analyzed to determine, in a populationand/or in a specific patient, triggering events related to inflation (orany other indication), and/or to VNS response from the patient. Suchresponses may be used as triggers to automatically or manually modifythe VNS. For example, as described in greater detail below withreference to FIGS. 54A-54I, an inflammatory stress, such as LPIinjection in a test animal, may result in a marked and detectable changein the neurogram, including in the frequency distribution of theneurogram during or immediately following the stress. In addition, theeffect of VNS may be detected in a neurogram (e.g., specifically, apatterned 40-50 Hz response following VNS). Changes in the neurogram(e.g., the frequency distribution) characteristic of either inflammatorystress or deviation from the VNS state may be used to gate activity ofthe implant (e.g., microstimulator). A processor, either in/on theimplant, or separate from the implant (e.g., remotely accessed) maymonitor the sensed information such as the neurogram and/or cardiacand/or respiratory signals and control operation of the microstimulatorbased on detected signals or deviation from expected signal patterns.The detected signals or signal patterns may be determined and/ormodified for an individual, or they may be determined based onpopulation studies.

For example, subject-specific triggering signals and/or patterns may bedetermined during an initial (e.g., open loop) period, and/or modifiedin an ongoing matter (semi closed-loop). A subject implanted with amicrostimulator may be monitored and the system may tag recorded signalswith labels indicating when the events have occurred. The subject maythemselves participate, e.g., reporting periods of pain, inflammation,etc., and these indicators may be used to identify characteristicsignals/patterns, and thereby train the system or modify an existingtraining.

Neural recordings can be recorded by the microstimulator or anotherrecording device. For example, if using the microstimulator to recordingthe electrical activity in the nerve, the microstimulator can bemodified to provide it with capability to capture compound actionpotentials (CAPs) and spike counting. For example, a neural recordingmay include a compound action potential and may evoke compound actionpotentials. A compound action potential is a recording of the potentialselicited directly by the stimulator depolarizing axons. Additionally oralternatively, the neurostimulator (microstimulator) may detect a(passive) neurogram, which is typically a longer epoch measure ofspontaneous firing. The microstimulator may passively use the existingstimulation electrodes (for recording, rather than or in addition tostimulation) during periods when the implant is not stimulating, torecord signals (e.g., neurograms) and/or use separate, dedicatedelectrodes. One modification to the microstimulator circuitry and/orprogramming is an improved amplifier having an adjustable gain, goingfrom 1× to 100× to 1,000×, to 10,000×, which allows the microstimulatorto detect very low level signals. The bandwidth can be from 1 Hz to 10KHz. A spike counter can be added, and the microstimulator can recordfrom batteries or indefinitely in the EM field cage. FIGS. 44A and 44Billustrate an embodiment of the modified microstimulator circuitry,which can be manufactured on a ceramic substrate. The ceramic substrateand circuitry can be mounted within a capsule and used as amicrostimulator. Other substrates can be used when the modifiedcircuitry has been finalized. FIG. 45 illustrates a schematic of themodified circuitry, which can have an extra capacitor and diodes toallow stimulation from large impedance electrodes. Additionally, theelectrodes can be configured to both stimulate and record, and themicroprocessor (MCU) can be programmed to compress and store data toovercome a 1200 bit/sec communication rate. In addition to the enhancedamplifier and spike counter, the microstimulator circuitry can have thefollowing variations. The amplifier gain can be increased to 100, 1K, or10K times the baseline. The recovery, common-mode rejection ratio(CMRR>80 dB), and the signal to noise ratio (SNR>60 dB) can be optimizedto capture neural activity in a similar manner to cochlear implantevoked potential systems. A matched filter can be used to detect spikesand a comparator can be used to count spikes. The ASIC can be designedto meet or exceed a 90 dB CMRR that is commonly built for other systems,such as EMG systems.

FIG. 46A illustrates an embodiment of an ASIC schematic that shows thestimulator, the improved amplifier, the matched filter, the comparator,and the spike counter. A neural signal can be detected from theelectrodes of the stimulator. The detected neural signal can beamplified, then passed through a matched filter, then sent to acomparator, and then to a spike counter. Additional system variationsinclude a larger battery to support sensing in addition to the deliveryof electrical stimulation, incorporation of a sensing ASIC, andmodification of the saddle/POD for different nerves or the addition of acuff or lead. FIG. 46B illustrates an alternative ASIC schematic whichin addition to the amplifier, matched filter, comparator, spikecounter/integrator, also includes a memory bank for storing counts, andoptionally, other portions of the neural signal that can be used tocharacterize the signal and determine the neural signature. In addition,a 3× or 4× mode can be used instead of a 2× mode, in order to increasestimulation voltage levels for less efficient stimulation modalities.The ASIC can include a timer that triggers or initiates the system totake measurements of the neural signal when the subject is sleeping. Theamplification, spike recognition, and thresholding results can be storedin the memory. The MCU can be triggered at a predetermined time aftercollection of the neural signal to process the results that are storedin memory, store the results in flash memory, and/or make therapyadjustments based on the characterization of the neural signature. Insome embodiments, the ASIC can be modified to make topology softwareswitchable allowing the same model to be used for multiple applications,thereby reducing development and test time and cost.

FIG. 47 is a flow chart of a method of performing closed loop vagusnerve stimulation. In step 4700, the neural signature, from a sensedneurogram, of the anti-inflammatory reflex is identified and the systemdetermines how it relates to accommodation during chronic VNS. Thesystem can determine how the neural signature relates to accommodationby generating a patient specific neural signature database during thecourse of treatment that includes neural signatures at various levels ofinflammation before and after treatment, including at times whereaccommodation is suspected of reducing the efficacy of treatment. Theprocedure can be implemented using a machine learning algorithm thatcontinuously adds sensed neural signatures to the database to furtherrefine the system. A sensed neural signature can be compared to theneural signature database to determine whether the patient is in a stateof accommodation. Alternatively or additionally, one or more featurescan be extracted from the neurogram, such as the signal amplitude,frequency and duration, and these features can be used for comparison.In some embodiments, the sensed neural signature can be compared to oneor more model neural signatures which represent various states ofaccommodation, such as no accommodation, minor accommodation, moderateaccommodation and severe accommodation. The model neural signatures canbe generated by pooling neural signature data from a group a patients.In some embodiments, the sensed neural signature can be compared to botha patient specific neural signature database and a model neuralsignature database. Once the system determines how the sensed neuralsignature relates to accommodation, the system can proceed to step 4702and deliver therapeutic dosing based on the sensed native or evokedvagus neurogram and/or the determined level of accommodation, where anevoked neurogram is taken subsequent delivery of the stimulation, and anative neurogram is taken at a time far enough removed from thestimulation that the neurogram signal is not caused by the stimulation.For example, if the sensed neural signature indicates moderateaccommodation, the electrical stimulus dosing can be modified. Forexample, the dosing can be delayed by increasing the off-time betweenstimulations, thereby reducing the effects from potentialover-stimulation of the vagus nerve. Alternatively, various stimulationparameters can be adjusted, such as pulse amplitude, frequency, width,duration and the like. In some embodiments and in some situations, itmay be desirable to increase pulse amplitude to compensate for reducedefficacy. However, while this may result in a short term therapeuticbenefit, it may exacerbate the accommodation problem. To counteraccommodation, the stimulation duration may be decreased, or asmentioned above, the off time can be increased, or the frequency can bevaried. Increasing the off-time because a low level of inflammation isdetected or in order to reduce overstimulation may also have the effectof extending battery life.

As discussed above, the characteristic neural signature of theinflammatory reflex can be identified. Neural recordings ofimmunological responses to various stimuli, such as LPS challenge, TNFlevels, induced disease, in the context of passive and active vagusnerve stimulation can be used to generate a neural signature databaseand to train the system to recognize a diseased state based on adetected neural signature. Additionally, patients suffering from aninflammatory episode or flare up can have a neural recording taken. Forexample, the datapad can include an option to take a neural recordingand allow the patient to annotate or categorize the level ofinflammation or inflammation related pain that is experience by thepatient at that time. In some embodiments, the patient may be instructedto take a neurogram according to a predetermine schedule and or atvarious levels of inflammation in order to construct a neural signaturedatabase and to train the system to be able to accurately categorize asensed neural recording. The therapeutic stimulus can be optimized tomaximize the physiologic response at minimal power and to utilize neuralfeedback on accommodation for the prevention or reduction oftachyphylaxis.

FIG. 48A illustrates a neurogram of the vagus nerve that allows therecording of nerve activity signatures after delivery of a stimuli,which can be LPS injection as shown, or another stimuli or condition asdescribed herein. The signature can be processed to extract variousparameters, such as the number of peaks or spikes greater than athreshold, which can be predetermined or can be relative to thedetermined baseline. In some embodiments, an amplitude threshold can beused to characterize the neural signal. In other embodiments, the systemfurther identifies the type of spikes along with the number of thespikes. Other characteristics of the spike which can be identifiedinclude the spike width and time-amplitude window, which can besubjected to a threshold. In some embodiments, the spikes are sorted byprinciple components. FIGS. 48B-48D illustrate single channel vagusnerve recordings after inflammatory challenge that illustrate lowfrequency spike characteristics that can be distinguished from theunderlying vagal tone, which has a frequency of about 35 to 55 Hz.Although illustrated in the time domain, the neural signals can bealternatively or additionally analyzed using a frequency spectrumanalysis in the frequency domain, which may facilitate removal ofvarious artifacts of know frequency, such as heart rate and respiration,while presenting low frequency spikes.

The neural signature of the vagus nerve or other target nerve may beobscured by various artifacts, including electrical signals from muscleactivation and the heart, some of which may be orders of magnitudegreater than the target signal. Selective filtering may be able toremove some of these artifacts, such as filtering signals occurringaround the frequency of the rate of respiration and the heart rate andother processes that occur at a regular frequency. In some embodiments,the neural signatures can be acquired while the patient is asleep inorder to minimize or reduce muscle activation, while still taking intoaccount the respiration and heart rate. The signal may be highlyvariable over time, which may be dealt with by constructing a patientspecific neural signature database which is continuously or periodicallyupdated over the course of treatment. In addition, a tripolar electrodecan be used for the microstimulator to reduce noise and improve the SNR.

In addition to vagus nerve activity, the system can be modified to senseadditional bioelectric activity including, but not limited to, heartrate, heart rate variability, respiratory rate, frequency domain aspectsof heart rate, vagal action potentials, vagal compound actionpotentials, frequency of detected action potentials, and frequencydomain components of vagal action potentials. Onboard or remoteprocessor to evaluate detected characteristics of detected bioelectricactivity activity. These detected characteristics may be evaluatedindividually or in combination. These signals may be detected using theelectrodes on the microstimulator, or can be detected with additionalelectrodes, which may be on leads which can be positioned in varioustissues. For example, an additional electrode may be desirable for thedetection of evoked potentials. Additional nerves may also be monitored,such as the spinal cord or sensory neurons involved in pain or stretchdetection.

FIGS. 49A and 49B illustrate embodiments of the system which can be usedin animal testing or in humans. For example, a unit that is compatiblewith humans may also be suitable for use in canines. A mouse acute unitcan utilize small cuff electrodes and a high voltage externalstimulator. A mouse chronic unit for implantation for a long duration,such as 6 months, can be based on a modified hybrid human unit thatproduces high voltages which are desirable when using small electrodes.FIG. 50 illustrates an embodiment of a microregulator capsule with theability to stimulate in the range of 20 to 3500 μA and to measureimpedances. External leads can be laser welded to the capsule forstimulation of smaller nerves or to record electrical signals from othernerves.

Example

Rats were anesthetized and maintained under anesthesia with isoflurane(1-3%). A bipolar cuff electrode was placed on the left cervical vagusnerve and electrocardiogram (ECG) needle electrodes were placedsubcutaneously. An electroneurogram (ENG; 20 kHz, 50,000× gain) wasrecorded, and an ECG (1.625 kHz, 1000× gain) was recorded with BiopacMP150 running under Acqknowledge v.4. The left vagus nerve wasstimulated at 1 mA, 250 us pulsewidth, 10 Hz for 30 seconds or with asham stimulation (0 mA). The rats were injected intraperitoneally (IP)with lipopolysaccharide (LPS; 1 mL of a LPS solution at a concentrationof 1.5 mg/mL). The data was imported into Labchart v.7 (ADlnstrument)for analysis. Spectral analysis (power) of ENG and ECG data between 0-65Hz was performed.

FIGS. 51-54I illustrate various ENGs taken of rat vagus nerves andconcurrently recorded ECGs. The ENG cover a baseline period before VNSor LPS challenge, a period after VNS, and a period after LPS challenge,allowing a comparison of the ENG at various states.

FIG. 51 illustrates an ENG from a rat vagus nerve that shows theunderlying vagal tone is approximately 35 to 55 Hz. FIGS. 52-53Billustrate an ENG, ECG and spectral analysis of the ENG from a ratchallenged with LPS. Spectral analysis of the ENG from 0 to 65 Hz showsa large increase in about the 25-45 Hz power shortly following LPSinjection. FIGS. 54A-54I illustrate an ENG, ECG and spectral analysis ofthe ENG from a rat on which VNS was performed and subsequentlychallenged with LPS. The spectrogram of the ENG from 0 to 65 Hz shows adistinct pattern of power increase between about 40 to 50 Hz followingVNS. The spectrogram also shows perturbation and eventual dampening ofpower following subsequent LPS injection. FIGS. 54D and 54G illustratespectral analysis of the ENG and ECG during a baseline period before VNSand LPS challenge. The baseline spectral analysis shows the presence oflarge cardiac related spikes in the ENG. FIGS. 54E and 54H illustratespectral analysis of the ENG and ECG post VNS but pre LPS challenge. Ascompared to baseline, the spectral analysis of the ENG shows that VNSresults in an increase in power at about 12 Hz, 38 Hz, and about 40 to50 Hz. FIGS. 54F and 54I illustrate spectral analysis of the ENG and ECGpost LPS challenge. As compared to pre LPS, there is a decrease in 38 Hzpower. There is also an artifact in 27 Hz power due to a heating padartifact.

In summary, an analysis of the ENGs and ECGs identified specificpatterns in the ENGs and ECGs that corresponded to: (1) an immunologicalchallenge, specifically LPS detection by the vagus nerve in the absenceof VNS; (2) a patterned resonance within the vagus nerve following vagusnerve stimulation; (3) an immunological challenge, specifically LPSdetection by the vagus, subsequent to VNS; and (4) an altered patternedresonance following VNS due to subsequent immunological challenge.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements, these features/elements should not be limitedby these terms, unless the context indicates otherwise. These terms maybe used to distinguish one feature/element from another feature/element.Thus, a first feature/element discussed below could be termed a secondfeature/element, and similarly, a second feature/element discussed belowcould be termed a first feature/element without departing from theteachings of the present invention.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical rangerecited herein is intended to include all sub-ranges subsumed therein.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

What is claimed is:
 1. A method of closed-loop modulation of aninflammatory reflex, the method comprising: sensing electrical activityon a vagus nerve during a baseline period from a microstimulatorimplanted around a cervical portion of the vagus nerve; sensingelectrical activity on the vagus nerve during an inflammatory episode;determining a neural signature for each of a plurality of inflammatorystates based on the sensed electrical activity from the baseline periodand the sensed electrical activity from the inflammatory episode;sensing electrical activity on the vagus nerve at a first time period;determining an inflammatory state based on a comparison of the sensedelectrical activity to a neural signature; and controlling one or morecharacteristic of stimulation of the microstimluator based on thedetermined inflammatory state, wherein the one or more characteristic ofstimulation is selected from the group consisting of: duration,intensity, frequency, on-time and off-time.
 2. The method of claim 1,wherein determining the neural signature for each of a plurality ofinflammatory states includes: performing a spectral analysis of thesensed electrical activity; and identifying changes in power of thesensed electrical activity at one or more frequencies.
 3. The method ofclaim 2, wherein the one or more frequencies are between 0 and 100 Hz.4. The method of claim 1, wherein determining the neural signature foreach of a plurality of inflammatory states includes counting electricalspikes.
 5. The method of claim 1, wherein determining the neuralsignature for each of a plurality of inflammatory states includessensing the electrical activity before and after applying stimulation tothe vagus nerve.
 6. The method of claim 1, wherein determining theneural signature for each of a plurality of inflammatory states includessensing electrical activity at various levels of inflammation.
 7. Themethod of claim 6, wherein sensing electrical activity at various levelsof inflammation includes measuring vagus nerve activity during periodswhen the microstimulator is not stimulating the vagus nerve.
 8. Themethod of claim 1, wherein determining the inflammatory state comprisesanalyzing compound action potentials (CAPs) in a neural recording. 9.The method of claim 8, wherein controlling one or more characteristic ofstimulation comprises modifying a treatment dosage based on the CAPs.10. The method of claim 1, wherein determining the neural signature foreach of a plurality of inflammatory states includes comparing the sensedelectrical activity to one or more model neural signatures.
 11. Themethod of claim 1, wherein determining the inflammatory state includesreceiving reported periods of pain from a patient.
 12. The method ofclaim 1, wherein recording the electrical activity includes recordingthe electrical activity a predetermined time after application each of aplurality of stimulations.
 13. An implantable microstimulator device fortreating chronic inflammation, the device comprising: a hermeticallysealed capsule body; at least two electrically conductive capsuleregions, wherein each region electrically connects to an electrode,wherein the electrodes are configured for applying stimulation to avagus nerve and for sensing electrical activity from the vagus nerve; apower source within the sealed capsule body; and a controller within thesealed capsule body configured to: sense electrical activity on a vagusnerve during a baseline period from the microstimulator device implantedaround the cervical portion of the vagus nerve; sense electricalactivity on the vagus nerve during an inflammatory episode; determine aneural signature for each of a plurality of inflammatory states based onthe sensed electrical activity from the baseline period and the sensedelectrical activity from the inflammatory episode; sense electricalactivity on the vagus nerve at a first time period; determine aninflammatory state based on a comparison of the sensed electricalactivity to a neural signature; and control one or more characteristicof stimulation of the microstimluator based on the determinedinflammatory state, wherein the one or more characteristic ofstimulation is selected from the group consisting of: duration,intensity, frequency, on-time and off-time.
 14. The implantablemicrostimulator device of claim 13, further comprising an ASIC withinthe capsule body having a spike counter for counting electrical spikesof the sensed electrical activity from the vagus nerve.
 15. Theimplantable microstimulator device of claim 14, further comprising amemory in communication with a spike counter for storing the counts ofthe spike counter.
 16. The implantable microstimulator device of claim13, wherein the electrode is a tri-polar, or a pseudotripolar, or atetrode electrode.
 17. The implantable microstimulator device of claim13, further comprising an ASIC within the sealed capsule body having avariable amplifier.
 18. The implantable microstimulator device of claim13, wherein the controller is configured to cause the electrodes toapply a treatment dosage based on minimizing deviation of a respiratorysignal.
 19. The implantable microstimulator device of claim 13, whereina treatment dosage is determined based on patient specific neuralsignatures at various levels of inflammation before and after treatment.20. A system for closed-loop modulation of an inflammatory reflex, thesystem comprising: an implantable microstimulator adapted to be appliedaround a cervical portion of a vagus nerve; at least one sensingelectrode on the implantable microstimulator configured to detectbioelectric activity on the vagus nerve; a controller configured to:sense electrical activity on a vagus nerve during a baseline period fromthe microstimulator device implanted around the cervical portion of thevagus nerve; sense electrical activity on the vagus nerve during aninflammatory episode; determine a neural signature for each of aplurality of inflammatory states based on the sensed electrical activityfrom the baseline period and the sensed electrical activity from theinflammatory episode; sense electrical activity on the vagus nerve at afirst time period; determine an inflammatory state based on a comparisonof the sensed electrical activity to a neural signature; and control oneor more characteristic of stimulation of the microstimluator based onthe determined inflammatory state, wherein the one or morecharacteristic of stimulation is selected from the group consisting of:duration, intensity, frequency, on-time and off-time.